ABCMdb

ABCC7 p.Gln1352His

ClinVar:	c.4056G>C , p.Gln1352His D , Pathogenic c.4056G>T , p.Gln1352His D , Likely pathogenic
CF databases:	c.4054C>G , p.Gln1352Glu (CFTR1) ? , The mutation was detected by DHPLC analysis and characterized by direct sequencing. We have seen it only twice, in over 3000 control chromosomes from Italian population. c.4056G>C , p.Gln1352His (CFTR1) ? , c.4056G>T , p.Gln1352His (CFTR1) ? , This change has been detected by SSCP/HD analysis and direct sequencing in one Spanish chromosome
Predicted by SNAP2:	A: D (63%), C: D (66%), D: D (85%), E: D (80%), F: D (80%), G: D (75%), H: D (85%), I: D (80%), K: D (85%), L: D (80%), M: D (66%), N: D (75%), P: D (91%), R: D (91%), S: D (66%), T: D (66%), V: D (66%), W: D (91%), Y: D (80%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, R: D, S: D, T: D, V: D, W: D, Y: D,

[switch to compact view]
Comments [show]

None has been submitted yet.

Publications
[hide] Polymorphisms of MRP1 (ABCC1) and related ATP-depe... Pharmacogenet Genomics. 2005 Aug;15(8):523-33. Conseil G, Deeley RG, Cole SP
Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters.
Pharmacogenet Genomics. 2005 Aug;15(8):523-33., [PMID:16006996]

Abstract [show]
Genetic variations in drug metabolizing enzymes and targets are established determinants of adverse drug reactions and interactions, but less is known about the role of genetic polymorphisms in membrane transport proteins. MRP1 (ABCC1) is one of 13 polytopic membrane proteins that comprise the 'C' subfamily of the ATP-binding cassette (ABC) superfamily of transport proteins. MRP1 and related ABCC family members, including MRP2, 3, 4 and 5 (ABCC2, 3, 4 and 5), each have a distinctive pattern of tissue expression and substrate specificity. Together, these five transporters play important roles in the disposition and elimination of drugs and other organic anions, and in maintenance of blood-tissue barriers, as confirmed by enhanced chemosensitivity of respective knockout mice. Moreover, Mrp2 (Abcc2) deficient animals display mild conjugated hyperbilirubinemia, corresponding to a human condition known as Dubin-Johnson syndrome (DJS). Naturally occurring mutations in MRP/ABCC-related drug transporters have been reported, some of which are non-synonymous single nucleotide polymorphisms. The consequences of the resulting amino acid changes can sometimes be predicted from in vitro site-directed mutagenesis studies or from knowledge of mutations of analogous (conserved) residues in ABCC proteins that cause DJS, Pseudoxanthoma elasticum (ABCC6), cystic fibrosis (CFTR/ABCC7) or persistent hyperinsulinemic hypoglycemia of infancy (SUR1/ABCC8). Continual updating of databases of sequence variants and haplotype analysis, together with in vitro biochemical validation assays and pharmacological studies in knockout animals, should make it possible to determine how genetic variation in the MRP-related transporters contributes to the range of responses to drugs and chemicals observed in different human populations.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
56 In the kidney, glomeruli and distal collecting tubules express MRP1, and, in the brain, MRP1 appears to form part of the drug permeability barrier Fig. 1 CF (CFTR/ABCC7) Q1291R E1228G Q1238R G1244E/V G1247R G1249R S1251N S1255P/L W1282G/R/C R1283K/M N1303K Y1307C E1321Q K1351E Q1352H R1268Q V1298F T1301I G1302R A1303P R1314W/Q G1321S R1339C Q1347H I1350L G1354R D1361N Q1382R A1450T R1347E R1351P V1359G/M S1368A G1377R G1382S R1392H R1419C R1435Q G1477R G1479R R1492W E1505K DJS (MRP2/ABCC2) NBD1 NBD2 COOH MEMBRANE MSD MSD MSD 12131415161710116 7 8 91 23 4 5TM H2 N Extracellular Intracellular PXE (ABCC6) PHHI (SUR1/ABCC8) Two-dimensional structure of MRP-related proteins. Login to comment

[hide] A haplotype-based molecular analysis of CFTR mutat... Hum Mol Genet. 2003 Sep 15;12(18):2321-32. Lee JH, Choi JH, Namkung W, Hanrahan JW, Chang J, Song SY, Park SW, Kim DS, Yoon JH, Suh Y, Jang IJ, Nam JH, Kim SJ, Cho MO, Lee JE, Kim KH, Lee MG
A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases.
Hum Mol Genet. 2003 Sep 15;12(18):2321-32., 2003-09-15 [PMID:12952861]

Abstract [show]
Aberrant membrane transport caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is associated with a wide spectrum of respiratory and digestive diseases as well as cystic fibrosis. Using a gene scanning method, we found 11 polymorphisms and mutations of the CFTR gene in the Korean population. Individual variants at these sites were analyzed by conventional DNA screening in 117 control and 75 patients having bronchiectasis or chronic pancreatitis. In a haplotype determination based on a Bayesian algorithm, 15 haplotypes were assembled in the 192 individuals tested. Several haplotypes, especially with Q1352H, IVS8 T5, and E217G, were found to have disease associations in a case-control study. Notably, a common polymorphism of M470V appears to affect the intensity of the disease association. Among the two haplotypes having IVS8 T5, the T5-V470 haplotype showed higher disease association than the T5-M470 haplotype. In addition, a Q1352H mutation found in a V470 background showed the strongest disease association. The physiological significances of the identified mutations were rigorously analyzed. Non-synonymous E217G and Q1352H mutations in the M470 background caused a 60-80% reduction in CFTR-dependent Cl(-) currents and HCO3(-) -transport activities. Surprisingly, the additional M470V polymorphic variant with the Q1352H mutation completely abolished CFTR-dependent anion transport activities. These findings provide the first evidence on the importance of CFTR mutations in the Asian population. Importantly, the results also reveal that interactions between multiple genetic variants in cis affect the final function of the gene products.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
4 Several haplotypes, especially with Q1352H, IVS8 T5, and E217G, were found to have disease associations in a case-control study. Login to comment
7 In addition, a Q1352H mutation found in a V470 background showed the strongest disease association. Login to comment
9 Non-synonymous E217G and Q1352H mutations in the M470 background caused a 60-80% reduction in CFTR-dependent ClÀ currents and HCO3 À -transport activities. Login to comment
10 Surprisingly, the additional M470V polymorphic variant with the Q1352H mutation completely abolished CFTR-dependent anion transport activities. Login to comment
44 In samples from patients, several other heteroduplexes were found including one in exon 22, which was identified as Q1352H (G to C change at nucleotide 4188). Login to comment
52 Genetic variants at several sites were found to be associated with bronchiectasis and/or chronic pancreatitis, the most notable being Q1352H. Login to comment
53 The heterozygote frequency of Q1352H was significantly higher in bronchiectasis (P ¼ 0.02) and chronic pancreatitis patients (P ¼ 0.005) than in the control group. Login to comment
72 (C) The genetic variation in exon 22 was identified as Q1352H (4188G > C) by bi-directional nucleotide sequencing. Login to comment
74 CFTR genetic variants analyzed in this study Variations found by TDGS Most common worldwide disease-causing mutations Reported disease-associated microsatellite À8G/C (50 UTR)a R117H (exon 4) T5-7,9 (IVS 8) (16) I125T (exon 4)b 621 þ 1G > T (intron 4) E217G (exon 6a)b F508del (exon 10) 1059C > T (exon 7, A309)a 1717-1G > A (intron 10) M470V (exon 10)b G542X (exon 11) I556V (exon 11)b G551D (exon 11) 2694T/G (exon 14a, T854)b R553X (exon 11) Q1352H (exon 22)b R1162X (exon 19) R1453W (exon 24)b W1282X (exon 20) N1303K (exon 21) Mutation names and nucleotide numbers are presented according to the Cystic Fibrosis Genetic Analysis Consortium (CFGAC; www.genet.sickkids.on.ca/). Login to comment
91 As expected from the genotype data, haplotype 4 containing Q1352H showed the strongest association with bronchiectasis and chronic pancreatitis in the Korean population (P ¼ 0.02 and P ¼ 0.008, respectively). Login to comment
105 As shown in Figure 2A, the protein expressions of mature glycosylated CFTR were significantly decreased in E217G and Q1352H mutations. Login to comment
107 Frequency of CFTR gene variants in the Korean population Variation Genotype Group (number) Healthy control (n ¼ 117) Bronchiectasis (n ¼ 47) Pancreatitis (n ¼ 28) Diallelic -8G/C þ/þ 105 44 22 þ/Àa 12 3 6 R117H þ/þ 116 47 28 þ/À 1 0 0 I125T þ/þ 116 46 27 þ/À 1 1 1 E217G þ/þ 114 43 27 þ/À 3 4b 1 1059C > T þ/þ 117 47 27 (A309) þ/À 0 0 1 M470V þ/þ 23 3 6 þ/À 52 28 14 À/À 42 16 8 I556V þ/þ 111 45 28 þ/À 6 2 0 2694T/G þ/þ 41 16 8 (T854) þ/À 51 27 14 À/À 25 4 6 Q1352H þ/þ 116 43 24 þ/À 1 4* 4** R1453W þ/þ 115 46 28 þ/À 2 1 0 Microsatellite T5-7,9 5/7 4 6* 2 (IVS 8) 6/7 0 1 0 7/7 110 39*c 26 7/9 3 1 0 Differences between control and disease groups were analyzed by a chi-square test. When an expected cell value was less than 5, Fisher`s exact test was used. Login to comment
114 Haplotype assembly Allele ID -8G/C R117H I125T E217G 1059C/T T5-7,9 M470V I556V 2694T/G Q1352H R1453W Group a M470V-2694T/G background Control, n (%) Bronchiectasis, n (%) Pancreatitis, n (%) 1 G R I E C WTb V I T Q R 121 (51.7) 47 (50.0) 24 (42.9) 2-1 2 G R I E C WT M I G Q R 78 (33.3) 25 (26.6) 18 (32.1) 1-2 3 C R I E C WT M I G Q R 11 (4.7) 3 (3.2) 5 (8.9) 1-2 4 G R I E C WT V I T H R 1 (0.4) 4 (4.3)* 4 (7.1)** 2-1 5 G R I E C 5 V I T Q R 2 (0.9) 5 (5.4)* 1 (1.8) 2-1 6 G R I G C WT M I G Q R 3 (1.3) 4 (4.3)c 1 (1.8) 1-2 7 G R I E C WT V V T Q R 5 (2.1) 2 (2.2) 0 (0.0) 2-1 8 G R I E C WT V I G Q R 4 (1.7) 1 (1.0) 0 (0.0) 2-2 9 G R I E C 5 M I G Q R 2 (0.9) 1 (1.0) 1 (1.8) 1-2 10 G R I E C WT M I G Q W 2 (0.9) 1 (1.0) 0 (0.0) 1-2 11 G R T E C WT V I T Q R 1 (0.4) 1 (1.0) 1 (1.8) 2-1 12 G R I E C WT M I T Q R 2 (0.9) 0 (0.0) 0 (0.0) 1-1 13 C R I E C WT V I G Q R 1 (0.4) 0 (0.0) 0 (0.0) 2-2 14 G H I E C WT V V T Q R 1 (0.4) 0 (0.0) 0 (0.0) 2-1 15 C R I E T WT M I G Q R 0 (0.0) 0 (0.0) 1 (1.8) 1-2 Total 234 (100.0) 94 (100.0) 56 (100.0) Haplotypes were assembled using a software based on the Bayesian algorithm (Haplotyper) (7). Login to comment
122 Compared with WT, the expression levels of E217G and Q1352H were reduced by 64 and 73%, respectively, when CFTR band intensities were normalized against those of the cis-gene product DHFR (Fig. 2B). Login to comment
129 Among them, Q1352H showed the largest decrease (by 71%) and R1453W showed the smallest decrease (by 37%) in whole cell ClÀ currents (Fig. 3C). Login to comment
134 Compared with WT, Po was significantly reduced in I556V (by 34%), Q1352H (by 55%), and R1453W (by 78%). Login to comment
138 In the case of Q1352H, both membrane expression and Po were decreased. Login to comment
145 Compared to the WT, E217G and Q1352H showed significant reductions in forskolin-stimulated ClÀ /HCO3 À exchange by 65 and 77%, respectively. Login to comment
146 Effects of M470V on Q1352H The Q1352H mutation showed the highest disease associations in the genotype data. Login to comment
147 Since Q1352H is appeared only in the V470 background in the tested population (Table 3), we made M470V changes in WTand Q1352H-CFTR clones and performed functional studies. Login to comment
148 As shown in Figure 5A, additional M470V change did not alter the protein expression levels in either WTor Q1352H-CFTR. Login to comment
149 However, additional M470V change in Q1352H abolished cAMP-activated ClÀ currents (Fig. 5C and D) and cAMP-activated ClÀ /HCO3 À exchanges (Fig. 5E and F) by 99 and 95%, respectively. Login to comment
176 Characteristics of CFTR mutants selected for functional studies Name Nucleotide change Exon Domain Evolutionary conservationa Possible disease associationb E217G 782A >G 6a EC2 b, h, r CF with pancreatic sufficiency (Polish), Panbronchiolitis (Japanese) I556V 1798A >G 11 NBD1 All seven species Chronic bronchitis (French) Q1352H 4188G > C 22 NBD2 All seven species CBAVD (Japanese), Panbronchiolitis (Japanese) R1453W 4489C > T 24 IC10 b, h, m, r, s Panbronchiolitis (Japanese) a Evolutionary conservations are compared in CFTR genes of bovine (b), dogfish (d), human (h), mouse (m), rabbit (r), sheep (s), and xenopus (x). Login to comment
186 Q1352H was found to be the most notable mutation in both case-control and molecular functional studies. Login to comment
191 However, its sequence is highly conserved in all vertebrates and the change of the last glutamine into histidine (Q1352H) evoked defects in protein Figure 4. Login to comment
196 Representative traces of Mock-, WTand Q1352H-transfected cells are shown in (A), and the results of five to six experiments for each mutant are summarized in (B). Login to comment
199 Effects of M470V on Q1352H mutant. Login to comment
200 M470V variation was introduced in the WT and the Q1352H clones and protein expressions and functional activities were measured using the protocols described in the legends of Figures 2-4. Login to comment
201 M470V change did not alter the protein expression levels in WTor Q1352H-CFTR (A, B). Login to comment
202 However, additional M470V change in Q1352H abolished cAMP-activated ClÀ currents (C, D) and ClÀ /HCO3 À exchanges (E, F). Login to comment
208 However, the strongly disease associated Q1352H mutation also decreased the protein expression and functional activities by only 70-80%, which was not much different from E217G when they were measured in the same haplotype background of M470 (Figs 2-4). Login to comment
209 Of interest, E217G was found to arise in the haplotype having a high activity type of M470 (haplotype 6), and Q1352H to arise in the low activity type of V470 (haplotype 4) in the real population. Login to comment
210 Therefore, combinatorial effects with M470V locus may influence the overall function of haploid gene products in Q1352H mutation. Login to comment
211 Indeed, molecular data of double mutagenesis showed a surprising result that the additional change of M470V in Q1352H abolished the anion transporting activities of CFTR protein (Fig. 5). Login to comment
213 A plausible scenario is that M470V and Q1352H might be involved in the cross talk and/or interaction between the two NBDs of CFTR (25,26), since M470V and Q1352H are located in the NBD1 and NBD2, respectively. Login to comment
226 In conclusion, CFTR mutations of M470V-Q1352H, IVS8 T5-M470V, and E217G are associated with bronchiectasis and chronic pancreatitis. Login to comment
259 The mutagenic primers were as follows: E217G, 50 -CTC CTC ATG GGG CTA ATC TGG GGG TTG TTA CAG GCG TCT G-30 M470V, 50 -CTG GAG CAG GCA AGA CTT CAC TTC TAA TGG TGA TTA TGG GAG-30 ; I556V, 50 -AGT GGA GGT CAA CGA GCA AGA GTT TCT TTA GCA AGG TGA AT-30 ; Q1352H, 50 -CCT AAG CCA TGG CCA CAA GCA CTT GAT GTG CTT GGC TAG-30 ; R1453W, 50 -GTG AAG CTC TTT CCC CAC TGG AAC TCA AGC AAG TGC AAG TCT-30 . Login to comment

[hide] Improved detection of cystic fibrosis mutations in... Hum Reprod. 2004 Mar;19(3):540-6. Epub 2004 Jan 29. Danziger KL, Black LD, Keiles SB, Kammesheidt A, Turek PJ
Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis.
Hum Reprod. 2004 Mar;19(3):540-6. Epub 2004 Jan 29., [PMID:14998948]

Abstract [show]
BACKGROUND: Accurate determination of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is critical for genetic counselling and treatment of obstructive azoospermia. Of concern is that detection rates with routine CFTR mutation panels vary widely depending on patient ancestry; and such panels have limited value for azoospermic patients, who are more likely to carry rare mutations. An alternative approach offers comprehensive, CFTR mutation analysis by a DNA sequence method. We investigated whether this method could improve CFTR detection rates in men with obstructive azoospermia in a prospective study of men with obstructive azoospermia and their partners who were referred for genetic counselling and testing at one of two institutions. METHODS: Sixteen patients with congenital absence of the vas deferens (CAVD, n = 14) or idiopathic obstructive azoospermia (n = 2) were studied. DNA from all patients was analysed for mutations by the DNA sequence method. In addition to this method, six men underwent CFTR analysis by a common 25 or 31 mutation panel coupled with poly T analysis. In 10 subjects, common mutation panel findings were inferred from DNA sequence method results. RESULTS: Overall, 12/16 (75%) azoospermic patients had one or more CFTR mutations and/or 5T alleles, including 12 mutations in 10 patients (two compound heterozygotes) and seven 5T alleles in six patients (one homozygote). The sequence method detected all mutations and three variants of unknown significance. By comparison, the common mutation panels detected only 3/12 mutations (25%) and 0/3 variants. CONCLUSION: The DNA sequence method detects more CFTR mutations than common mutation panels. Given the serious, clinical consequences of transmitting such mutations, this study underscores the importance of accurate, CFTR mutation detection in men with obstructive azoospermia and their partners.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
85 Cauc. Het. * DF508/R117H Mutation/mutation Yesd 7 CBAVD Asian-Indian Het. Negative Het. V456A Mutationc No 8 CBAVD Asian Negative * Het. Q1352H Mutation Nod 9 CBAVD Asian Negative * Negative No mutation detected Yes 10 CBAVDb N.E. Cauc./ Asian/Ashkenazi Negative * I556V/2752±26A®G Mutation/mutation Nod 11 CBAVD Hispanic Homozygous * Het. W1098C Mutation Nod 12 CBAVD Asian Negative Negative Het. 3499+25C®G Variant of unknown signi®cance No 13 CUAVD Hispanic Negative * Negative No mutation detected Yes 14 CBAVDb N.E. Cauc. Negative * Negative No mutation detected Yes 15 Idiopathic obstruction Asian-Indian Negative * Het. I807M Mutationc Nod 16 Idiopathic obstruction N.E. Cauc. Het. * Het. DF508 Mutation Yesd *Analysis not done. Login to comment
121 Mutations and variants of unknown signi®cance detected in 16 patients with CAVD Detection method 31 common mutation panel and poly T analysis Sequence method and poly T analysis Mutations 5T 7 7 DF508 2 2 R117H 1 1 P750L ± 1 V201M ± 1 Q1352H ± 1 I556V ± 1 2752±26A®G ± 1 W1098C ± 1 I807M ± 1 V456A ± 1 V520I ± 1 Variants of unknown signi®cance 1717±4A®G ± 1 3601±3C®A ± 1 3499+25C®G ± 1 Total 10 22 the vas deferens is particularly susceptible to the decreased levels of CFTR protein product. Login to comment

[hide] Genetic evidence for CFTR dysfunction in Japanese:... J Med Genet. 2004 May;41(5):e55. Fujiki K, Ishiguro H, Ko SB, Mizuno N, Suzuki Y, Takemura T, Yamamoto A, Yoshikawa T, Kitagawa M, Hayakawa T, Sakai Y, Takayama T, Saito M, Kondo T, Naruse S
Genetic evidence for CFTR dysfunction in Japanese: background for chronic pancreatitis.
J Med Genet. 2004 May;41(5):e55., [PMID:15121783]

Abstract [show]

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
136 For example, polythymidine (poly-T) and TG dinucleotide repeats, (TG)n, at the junction of intron 8 and exon 9 influence transcription and thereby reduce the amount of normal CFTR protein.19 20 The M/V polymorphism at position 470 affects the function of the CFTR protein.20 In order to understand the genetic background for CFTR dysfunction in chronic pancreatitis in Japanese, we first analysed patients with chronic pancreatitis and healthy individuals for 20 CF mutations that are common in whites, along with 9 CF causing and 2 other non-CF causing (Q1352H and R1453W) mutations commonly found in Japanese. Login to comment
210 N These genetic backgrounds, together with a high association of Q1352H (12.3% in chronic pancreatitis patients v 3.7% in controls) or R1453W (6.2% v 3.1%), may explain the association of CFTR dysfunction and chronic pancreatitis in Japan where CF is very rare. Login to comment
219 The nine CF causing (R75X, Q98R, M152R, R347H, L441P, L571S, D979A, H1085R, and T1086I) and two non-CF causing (Q1352H and R1453W) mutations in Japanese6 22-24 were screened by SNP typing with a Masscode system (Shimadzu, Kyoto, Japan) and confirmed by sequence analysis in positive and equivocal cases. Login to comment
224 However, Q1352H and R1453W, both of which were originally identified in Japanese patients with diffuse panbronchiolitis,6 were found in one allele of both control and patients. Q1352H was found in eight patients with chronic pancreatitis (six alcoholic and two idiopathic); the frequency of Q1352H in chronic pancreatitis (12.3%) was significantly (p = 0.015) higher than that of controls (3.7%; 6 in 162 subjects). Login to comment
248 Association of 5T, Q1352H, and R1453W with genotypes of (TG)m/n-M470V Fig 3 summarises the frequency distribution of normal subjects and patients with chronic pancreatitis based on the genotypes of the TG repeats and M470V. Login to comment
249 5T was associated with (TG)12/13-M/V470 in two normal subjects and with (TG)12/12-M/V470 in two alcoholic patients. Q1352H was present in patients with (TG)11/11-V/V470 (three alcoholic and two idiopathic), (TG)11/12-M/V470 (6 normal and 2 alcoholic), and (TG)11/12-V/V470 (one alcoholic). Login to comment
253 However, we found a significantly higher accumulation (12.3%) of the Q1352H allele in patients with chronic pancreatitis, though it was also observed in healthy subjects (3.7% in Japanese and 0.9% in Korean). Login to comment
254 Glutamine at 1352 is located in the second nucleotide binding fold of CFTR,1 and its change to histidine (Q1352H) causes reduction in both protein expression and channel activity of CFTR.25 This mutation has been found in Japanese patients with CBAVD (25%), and in Korean patients with chronic pancreatitis (14.3%) and bronchiectasis (11.8%).25 The other mutation, R1463W, affects channel activity but its overall effect on CFTR function appears to be mild.25 One patient homozygous for R1453W showed no clinical manifestations other than idiopathic pancreatitis. Login to comment
289 Indeed, the Q1352H allele was found in three alcoholic and two idiopathic pancreatitis patients with the (TG)11/11-V/V470 haplotype (fig 3). Login to comment
291 The Cl2 channel activity is almost completely abolished in cells that expressed the V470-Q1352H CFTR.25 As Q1352H was always present in the V470 background, this allele cannot produce functional CFTR proteins. Login to comment
292 Thus, we can estimate that the association of Q1352H in the V/V470 genotype reduces the total CFTR function to about 25% of the wild type. Login to comment
301 Association of other mutations, such as Q1352H and R1453W, may further reduce CFTR function. Login to comment

[hide] Do CFTR gene polymorphisms determine the susceptib... Intern Med. 2004 Dec;43(12):1093-4. Naruse S
Do CFTR gene polymorphisms determine the susceptibility to alcoholic chronic pancreatitis?
Intern Med. 2004 Dec;43(12):1093-4., [PMID:15645635]

Abstract [show]

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
21 Third, some polymorphisms common in Japanese (Q1352H and R1453W) are often associated with idiopathic pancreatitis with the (TG)11/11 genotype (7), which probably result in a considerable loss of CFTR function (5). Login to comment

[hide] Cystic fibrosis in Korean children:a case report i... J Korean Med Sci. 2005 Feb;20(1):153-7. Ahn KM, Park HY, Lee JH, Lee MG, Kim JH, Kang IJ, Lee SI
Cystic fibrosis in Korean children:a case report identified by a quantitative pilocarpine iontophoresis sweat test and genetic analysis.
J Korean Med Sci. 2005 Feb;20(1):153-7., [PMID:15716623]

Abstract [show]
Cystic fibrosis (CF) is inherited as an autosomal recessive trait, and the mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene contributes to the CF syndrome. Although CF is common in Caucasians, it is known to be rare in Asians. Recently, we experienced two cases of CF in Korean children. The patients were girls with chronic productive cough since early infancy. Chest computed tomography showed the diffuse bronchiectasis in both lungs, and their diagnosis was confirmed by the repeated analysis of a quantitative pilocarpine iontophoresis test (QPIT). The sweat chloride concentrations of the first patient were 108.1 mM/L and 96.7 mM/L. The genetic analysis revealed that she was the compound heterozygote of Q1291X and IVS8 T5-M470V. In the second case, the sweat chloride concentrations were 95.0 mM/L and 77.5 mM/L. Although we performed a comprehensive search for the coding regions and exon-intron splicing junctions of CFTR gene, no obvious disease-related mutations were detected in the second case. To our knowledge, this is the first report of CF in Korean children identified by a QPIT and genetic analysis. The possibility of CF should be suspected in those patients with chronic respiratory symptoms even in Korea.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
121 For example, Q1352H mutation showed about 0.9% heterozygote frequencies in the control Korean population and was associated with the chronic bronchiectasis as a haplo-insufficiency form. Login to comment

[hide] Mutation analysis of SPINK1 and CFTR gene in Korea... Dig Dis Sci. 2005 Oct;50(10):1852-6. Lee KH, Ryu JK, Yoon WJ, Lee JK, Kim YT, Yoon YB
Mutation analysis of SPINK1 and CFTR gene in Korean patients with alcoholic chronic pancreatitis.
Dig Dis Sci. 2005 Oct;50(10):1852-6., [PMID:16187186]

Abstract [show]
Several genetic mutations have been reported to increase susceptibility to chronic pancreatitis. However, their roles in alcoholic chronic pancreatitis are controversial. We investigated the prevalence of SPINK1 N34S and new CFTR Q1352H mutations in alcoholic chronic pancreatitis in Korea. Forty-three patients with alcoholic chronic pancreatitis were enrolled and 35 healthy individuals served as controls. The SPINK1 N34S mutation was detected by the PCR-RFLP technique. The CFTR Q1352H mutation was examined with PCR direct sequencing. Mean age of chronic pancreatitis and control groups was 53.2 and 51.3 years, respectively. A SPINK1 N34S was detected as a heterozygote in one (2.4%) patient with alcoholic chronic pancreatitis and a heterozygote CFTR Q1352H was detected in one other patient. In the control population, neither SPINK1 nor CFTR mutation was detected. This study shows that SPINK1 N34S and CFTR Q1352H mutations are uncommon and do not play an important role in chronic alcoholic pancreatitis in Korea.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
3 We investigated the prevalence of SPINK1 N34S and new CFTR Q1352H mutations in alcoholic chronic pancreatitis in Korea. Login to comment
6 The CFTR Q1352H mutation was examined with PCR direct sequencing. Login to comment
8 A SPINK1 N34S was detected as a heterozygote in one (2.4%) patient with alcoholic chronic pancreatitis and a heterozygote CFTR Q1352H was detected in one other patient. Login to comment
10 This study shows that SPINK1 N34S and CFTR Q1352H mutations are uncommon and do not play an important role in chronic alcoholic pancreatitis in Korea. Login to comment
30 Recently, Q1352H in exon 22 showed the strongest association with idiopathic chronic pancreatitis in the Korean population (25). Login to comment
31 In order to investigate the role of genetic mutations in the pathogenesis of alcoholic chronic pancreatitis, we examined the prevalence of SPINK1 (N34S) and CFTR (Q1352H) mutations in alcoholic chronic pancreatitis in Korea. Login to comment
52 The CFTR exon 22 mutation (Q1352H) was examined by sequencing after PCR. Login to comment
57 If the mutation of Q1352H was found, reverse sequencing with primer 5 -GGA TCC AAA TGA GCA CTG GGT TC-3 was performed to confirm the result. Login to comment
71 Mutational Analysis of CFTR Q1352H. Login to comment
73 A heterozygous Q1352H mutation of CFTR was detected in one (2.4%) patient with alcoholic Fig 1. Login to comment
81 (B) DNA sequence electrospherograms demonstrating a disease-associated CFTR Q1352H mutation. Login to comment
97 A recent study showed that the new CFTR Q1352H mutation was found in 19% of Korean patients with idiopathic chronic pancreatitis (25). Login to comment
98 So we investigated whether the CFTR Q1352H mutation is also associated with alcoholic chronic pancredatitis. Login to comment
99 The CFTR Q1352H mutation was detected in only 1 of 43 patients with alcoholic chronic pancreatitis in this study. Login to comment
114 In conclusion, this study shows that CFTR Q1352H and SPINK1 N34S mutations do not play a major role in chronic alcoholic pancreatitis in Korea. Login to comment

[hide] Detection of F508del mutation in cystic fibrosis t... Singapore Med J. 2006 Feb;47(2):129-33. Zilfalil BA, Sarina S, Liza-Sharmini AT, Oldfield NJ, Stenhouse SA
Detection of F508del mutation in cystic fibrosis transmembrane conductance regulator gene mutation among Malays.
Singapore Med J. 2006 Feb;47(2):129-33., [PMID:16435054]

Abstract [show]
INTRODUCTION: Cystic fibrosis (CF) is one of the common genetic disorders in the western world. It has been reported to be very rare in Asian populations. According to the Cystic Fibrosis Genetic Analysis Consortium, more than 1,000 mutations of the CF gene have been identified. The CF gene, named the cystic fibrosis transmembrane conductance regulator (CFTR), is located on chromosome 7 and composed of 27 exons. This study aims to detect possible CFTR gene mutations in Malays. METHODS: We analysed 50 blood samples from healthy Malays with no symptoms of CF. DNA was extracted from blood using commercially available extraction kits (Eppendorf, Germany). Identification of CFTR gene mutation was performed using the CF OLA (Oligonucleotide Ligation Assay) kit (Applied Biosystems, USA). The PCR-ligation products were electrophoresed on eight percent sequagel using an ABI PRISM 377 genetic analyser (Applied Biosystems, USA). Electrophoresis data was analysed using the Genotyper software and a report of the CF genotype for all loci tested was created using the CF Genotyper Template software. Out of 50, one sample (two percent) was detected to have the F508del mutation (3bp deletion at exon 10), which is one of the most common CFTR gene mutations in Caucasians. RESULTS: The F508del mutation allele was detected in one subject. This indicates that she was a CF carrier. CONCLUSION: We report the finding of a carrier of the F508del mutation of the CFTR gene in the Malay population. Our finding revealed that CF could also affect the Malay population. Larger studies are necessary to determine the exact gene frequency of this population.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
75 Anzai et al(5) found three missense mutations (W216X, G1349S, Q1352H) in seven CFTR alleles and 5T allele was positive in 11 of 38 CFTR alleles among Japanese patients with congenital bilateral absence of the vas deferens (CBAVD). Login to comment

[hide] Identification of CFTR, PRSS1, and SPINK1 mutation... Pancreas. 2006 Oct;33(3):221-7. Keiles S, Kammesheidt A
Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis.
Pancreas. 2006 Oct;33(3):221-7., [PMID:17003641]

Abstract [show]
OBJECTIVES: Chronic pancreatitis is a progressive inflammatory disorder leading to irreversible exocrine and/or endocrine impairment. It is well documented that mutations in the cationic trypsinogen (PRSS1) gene can cause hereditary pancreatitis. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) and the serine protease inhibitor Kazal type 1 (SPINK1) genes are also associated with pancreatitis. METHODS: We analyzed 381 patients with a primary diagnosis of chronic or recurrent pancreatitis using the Ambry Test: Pancreatitis to obtain comprehensive genetic information for the CFTR, SPINK1, and PRSS1 genes. RESULTS: The results identified 32% (122/381) of patients with 166 mutant CFTR alleles, including 12 novel CFTR variants: 4375-20 A>G, F575Y, K598E, L1260P, G194R, F834L, S573C, 2789 + 17 C>T, 621+83 A>G, T164S, 621+25 A>G, and 3500-19 G>A. Of 122 patients with CFTR mutations, 5.5% (21/381) also carried a SPINK1 mutation, and 1.8% (7/381) carried a PRSS1 mutation. In addition, 8.9% (34/381) of all patients had 1 of 11 different SPINK1 mutations. Another 6.3% (24/381) of the patients had 1 of 8 different PRSS1 mutations. Moreover, 1.3% of the patients (5/381) had 1 PRSS1 and 1 SPINK1 mutation. A total 49% (185/381) of the patients carried one or more mutations. CONCLUSIONS: Comprehensive testing of the CFTR, PRSS1, and SPINK1 genes identified genetic variants in nearly half of all subjects considered by their physicians as candidates for genetic testing. Comprehensive test identified numerous novel variants that would not be identified by standard clinical screening panels.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
83 Patients With SPINK1 and CFTR Mutations SPINK Mutation 1 SPINK Mutation 2 SPINK1 Mutation 3 CFTR Mutation 1 CFTR Mutation 2 No. of Patients 5¶UTR-147 A9G W1282X 1 5¶UTR-41 G9A 5¶UTR-41 G9A D1445N 1 5¶-41 G9A D1270N R74W 1 5¶UTR-81 C9T deltaF508 5T 1 IVS3+184 T9A S1235R 1 IVS3+184 T9A 5T 1 IVS3+184 T9A deltaF508 5T 1 IVS-72delCT R75X 1 L12F IVS3+90 A9T 296+28 A9G 1 L12F IVS3+90 A9T 4375-20 A9G 1 M1R 5¶UTR-147 A9G 5T 1 N34S IVS3-66-65insTTTT N37S Q1352H 1 N34S IVS3-66-65insTTTT L997F 1 N34S 5T 1 N34S IVS3-66-65insTTTT 5T 3 N34S IVS3-66-65insTTTT IVS1-37T 9C deltaF508 R117H 1 N34S IVS3-66-65insTTTT IVS1-37T9C R117H 5T 1 N34S IVS3-66-65insTTTT 621+83 A9G 1 N34S IVS3-66-65insTTTT IVS1-37T9C deltaF508 S1235R 1 Total patients 21 CFTR mutations in boldface would not have been detected by the ACOG/ACMG mutation panel. Login to comment
113 G208A A 12-year-old Asian boy with pancreatitis was found to be homozygous for the G9C substitution in codon 208 of the PRSS1 gene. This changes a glycine to an alanine within exon 5. This patient was also found to carry the deltaF508 and Q1352H mutations in the CFTR gene. Therefore, this patient is affected with a form of CF, and the G208A variant in the PRSS1 gene may represent a benign sequence variation. Login to comment
116 Patients With CFTR and PRSS1 Mutations CFTR Mutation 1 CFTR Mutation 2 PRSS1 Mutation 1 PRSS1 Mutation 2 No. of Patients 5T E79K 1 5T R122H 1 2789+17 C9T C139S 1 deltaF508 N29I 1 deltaF508 Q1352H G208A G208A 1 G551D R122H 1 T908N IVS4-8 C9T IVS4-11 C9T 1 Total patients 7 CFTR mutations in boldface would not have been detected by the ACOG/ACMG mutation panel. Login to comment

[hide] Is genetic analysis helpful for diagnosing chronic... J Gastroenterol. 2007 Jan;42 Suppl 17:60-5. Naruse S, Fujiki K, Ishiguro H
Is genetic analysis helpful for diagnosing chronic pancreatitis in its early stage?
J Gastroenterol. 2007 Jan;42 Suppl 17:60-5., [PMID:17238030]

Abstract [show]
Diagnosis of chronic pancreatitis in its early stage is an extremely difficult task. If the genetic predispositions are identified, it may help make possible the earlier diagnosis of chronic pancreatitis or the detection of patients at risk. There are two major hypotheses about the pathogenesis of chronic pancreatitis known as the "necrosis-fibrosis" and "pancreatic stone protein" hypotheses. Recent molecular and genetic evidence suggests that both pathways contribute to the pathogenesis of chronic pancreatitis. Chronic pancreatitis may be caused by either increased proteolytic activity [the cationic trypsinogen (PRSS1) gene] or decreased protease inhibition (the pancreatic secretory trypsin inhibitor (PSTI) gene]. The impaired pancreatic duct function [cystic fibrosis transmembrane conductance regulator (CFTR) gene] may also be involved in the pathogenesis of the disease. Except for PRSS1 mutations, the known genetic risk for chronic pancreatitis is not high. The high individual variability and low incidence of chronic pancreatitis suggest that yet unidentified genetic and environmental factors are important. Further genetic analysis is necessary for understanding the pathogenesis of chronic pancreatitis, which may be helpful for the earlier diagnosis of the juvenile- or young-onset disease.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
43 In an initial screening study, common CF-causing mutations were not identified in either patients with chronic pancreatitis or control subjects.28 However, non-CF causing mutations (Q1352H and R1453W) are highly associated with chronic pancreatitis. Login to comment
44 Furthermore, these mutations are on the same allele as the M470V variant, which has low (~60%) intrinsic chloride channel activities.29 The Q1352H mutation in the M470 background causes a 60%-80% reduction in CFTR-dependent Cl- currents and completely abolishes them in the M470V variant.30 Therefore, as in whites, CFTR mutations/polymorphisms are likely to be associated with chronic pancreatitis in Japanese, although mutations may differ depending on ethnic origins. Login to comment

[hide] Detection of cystic fibrosis transmembrane conduct... Hum Reprod. 2007 May;22(5):1285-91. Epub 2007 Feb 28. Ratbi I, Legendre M, Niel F, Martin J, Soufir JC, Izard V, Costes B, Costa C, Goossens M, Girodon E
Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling.
Hum Reprod. 2007 May;22(5):1285-91. Epub 2007 Feb 28., [PMID:17329263]

Abstract [show]
BACKGROUND: Mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene have been widely detected in infertile men with congenital bilateral absence of the vas deferens (CBAVD). Despite extensive analysis of the CFTR gene using varied screening methods, a number of cases remain unsolved and could be attributable to the presence of large gene rearrangements, as recently shown for CF patients. METHODS: We carried out a complete CFTR gene study in a group of 222 CBAVD patients with strict diagnosis criteria and without renal anomaly, and searched for rearrangements using a semi-quantitative assay in a subgroup of 61 patients. RESULTS: The overall mutation detection rate was 87.8%, and 82% of patients carried two mutations. Ten out of the 99 different mutations accounted for 74.6% of identified alleles. Four large rearrangements were found in patients who already carried a mild mutation: two known partial deletions (exons 17a to 18 and 22 to 23), a complete deletion and a new partial duplication (exons 11 to 13). The rearrangements accounted for 7% of the previously unknown alleles and 1% of all identified alleles. CONCLUSIONS: Screening for rearrangements should be part of comprehensive CFTR gene studies in CBAVD patients and may have impacts on genetic counselling for the patients and their families.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
50 CFTR mutations were detected in 387 out of 444 alleles (87.2%), most of them being previously described in patients with CF of varying severity, CBAVD or other CFTR diseases: 45% of identified alleles consisted of severe CF mutations (e.g. F508del, W1282X, 2183AA.G); 13.8% of mild or variable CF mutations (e.g. L206W, 3272-26A.G, R117H, D1152H); 36.7% of mild CFTR defects which are currently not considered CF-causing (e.g. IVS8(T)5, Q1352H, the complex alleles [D443Y;G576A;R668C] and [R74W;D1270N]) and 4.5% of rare missense mutations whose effect is difficult to predict (e.g. A959V, G1069R, V1153E). Login to comment

[hide] Spectrum of mutations and variants/haplotypes of C... Clin Genet. 2007 Jun;71(6):530-9. Chang MC, Chang YT, Wei SC, Tien YW, Liang PC, Jan IS, Su YN, Wong JM
Spectrum of mutations and variants/haplotypes of CFTR and genotype-phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis.
Clin Genet. 2007 Jun;71(6):530-9., [PMID:17539902]

Abstract [show]
Mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene have been reported in patients with chronic pancreatitis. The authors examine whether the mutations and haplotypes of CFTR will increase the risk of developing idiopathic chronic pancreatitis (ICP) in Chinese and their genotype and phenotype correlations. Seventy-eight patients with ICP and 200 geographically and ethnically matched controls in Taiwan were analyzed. The entire 27 coding and intronic regions of the CFTR gene were identified using heteroduplex analytical techniques and confirmed by sequencing analysis. The presence of 125G/C, 1001+10C>T, IVSTn(TG)m, 1540A>G, c2694T>G, and c4521G>A were determined by directing sequencing. Abnormal CFTR allele was found to be thrice as frequent in ICP patients as in controls (22/156 vs 19/400, p < 0.0001). T5 allele was associated with early onset of ICP. In six-loci haplotype analysis, 13 common haplotypes were assembled in the 278 individuals tested. The 125G/1001+11C/TG12/470M/2694T/4521G haplotype was associated with risk of ICP (odds ratio 11.3; 95% confidence interval 2.3-54.6, p = 0.008) in Chinese. The mutation spectrum is different from other ethnic groups. A population-specific panel of CFTR changes should be recommended for targeted populations including ICP in Chinese. It is important to design suitable screening programs for different populations.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
97 These mutations include I556V, G to A 3849145, N287Y, I125T, E217G, S895N, G1O69R, and Q1352H that have been found in patients with CP or CBAVD (http://www.genet. Login to comment
109 (%) in ICP Controls (%) I556V Exon 11 A to G 1798 Amino acid substitution 7 (8.9) 2 (1) IVS8-5T Intron 8 deletaion of 2T between 1342-12 and 1342-6 Aberrant splicing 6 (7.7) 14 (7) G to A 3849145 Intron 19 G to A at 3849145 mRNA splicing defect 3 (3.8) 2 (1) N287Y Exon 6b A to T 991 Amino acid substitution 2 (2.6) 00 (0) I125T Exon 4 T to C 506 Amino acid substitution 1 (1.3) 00 (0) E217G Exon 6a A to G 782 Amino acid substitution 1 (1.3) 00 (0) S895N Exon 15 G to A 2816 Missense mutation 1 (1.3) 00 (0) G1O69R Exon 17b G to A 3337 Amino acid substitution 1 (1.3) 00 (0) Q1352H Exon 22 G to C at 4188 Amino acid substitution 0 (0.0) 1 (0.5) ICP, idiopathic chronic pancreatitis. Login to comment
157 All our mutations are belonging to Ômild` mutations compatible with previous studies (6), including I556V, G to A 3849145, I125T, E217G, N287Y, S895N, G1O69R, and Q1352H. Login to comment
170 Q1352H and E217G and M470V are considered to be strongly associated with chronic pancreatitis in Korean (9). Login to comment
171 I556V, I125T and Q1352H are reported to be associated chronic pulmonary disease from Singapore (35). Login to comment
172 In our study, only one control subject with Q1352H, which implied that the Q1352H might not associated with ICP in Chinese. Login to comment

[hide] Too much salt, too little soda: cystic fibrosis. Sheng Li Xue Bao. 2007 Aug 25;59(4):397-415. Quinton PM
Too much salt, too little soda: cystic fibrosis.
Sheng Li Xue Bao. 2007 Aug 25;59(4):397-415., 2007-08-25 [PMID:17700961]

Abstract [show]
Cystic fibrosis (CF) of the pancreas is the most widely accepted name of the most common fatal inherited single gene defect disease among Caucasians. Its incidence among other races is thought to be significantly less, but mutations in the gene have been reported in most, if not all, major populations. This review is intended to give general concepts of the molecular as well as physiological basis of the pathology that develops in the disease. First, an overview of the organ pathology and genetics is presented, followed by the molecular structure of the gene product (cystic fibrosis transmembrane conductance regulator, CFTR), its properties, functions, and controls as currently understood. Second, since mutations appear to be expressed primarily as a defect in electrolyte transport, effects and mechanisms of pathology are presented for two characteristically affected organs where the etiology is best described: the sweat gland, which excretes far too much NaCl ("salt") and the pancreas, which excretes far too little HCO3(- )("soda"). Unfortunately, morbidity and mortality in CF develop principally from refractory airway infections, the basis of which remains controversial. Consequently, we conclude by considering possible mechanisms by which defects in anion transport might predispose the CF lung to chronic infections.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
32 In surveys in Japan[31] , Korea[32] , and Vietnam[33] , no ΔF508 mutations were detected, but among Koreans screened on the basis of bronchiectasis or chronicpancreatitis, three mutations, Q1352H, E217G, and IVS8-T5 appearing with a M470V allele were associated with disease[32] . Login to comment

[hide] Primary sclerosing cholangitis in childhood is ass... J Pediatr. 2007 Sep;151(3):255-9. Epub 2007 Jul 24. Pall H, Zielenski J, Jonas MM, DaSilva DA, Potvin KM, Yuan XW, Huang Q, Freedman SD
Primary sclerosing cholangitis in childhood is associated with abnormalities in cystic fibrosis-mediated chloride channel function.
J Pediatr. 2007 Sep;151(3):255-9. Epub 2007 Jul 24., [PMID:17719933]

Abstract [show]
OBJECTIVE: To determine whether primary sclerosing cholangitis (PSC) in childhood is associated with abnormalities in cystic fibrosis transmembrane conductance regulator (CFTR). STUDY DESIGN: Subjects with PSC diagnosed in childhood (n = 20) were recruited from Children's Hospital. Subjects had testing with sweat chloride concentration, nasal transmembrane potential difference, and extensive genetic analysis of the CFTR gene. Disease control subjects consisted of 14 patients with inflammatory bowel disease alone and no liver disease. t tests were performed to determine statistical significance. RESULTS: In the PSC group, CFTR chloride channel function (deltaChloride free + isoproterenol) was markedly diminished at -8.6 +/- 8.2 mV (reference range: -24.6 +/- 10.4 mV). In contrast, disease control subjects had normal function, at -17.8 +/- 9.7 mV (P = .008). Sweat chloride concentration in subjects with PSC was greater than in disease control subjects (20.8 +/- 3.4 mmol/L vs 12.0 +/- 1.6 mmol/L, P = .045). Comprehensive CFTR genotyping revealed that 5 of 19 (26.3%) subjects with PSC had a CFTR mutation or variant, compared with 6 of 14 (42.9%) disease control subjects. CONCLUSIONS: There is a high prevalence of CFTR-mediated ion transport dysfunction in subjects with childhood PSC.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
90 Mutations/Variants Polymorphism 1540 locus T Tract Sweat chloride (mmol/L) ⌬Cl ؉ Iso (mV)* PSC 1 GG 7/7 20.2 -1.2 2 GG 7/7 19.7 -17.3 3 R75Q AA 7/7 14.8 -3.9 4 4521G/A(8T/9T) AA 7/7 19.4 -13.3 5 2694T/G AG 7/7 NP NP 6 GG 7/7 5.1 -12.5 7 NP 5.8 -17.8 8 AA 7/7 9.9 -12.8 9 E725K AG 7/7 56.3 -5.1 10 R75Q AA 7/7 30.3 -5.5 11 4006 - 200G/A, 1233A/T AA 7/9 32.1 -29 12 2694T/G AG 7/7 8.7 -2.4 13 4521G/A, 4700T8/9 AG 7/7 4.8 -3.8 14 1525 - 61A/G AG 7/9 45.3 -2.2 15 3030G/A GG 7/7 18.6 -0.45 16 AA 7/7 7.6 -4.5 17 R75Q AG 7/9 21.6 -1.8 18 1001 ϩ 11C/T AG 7/9 45 1.2 19 AA 7/7 11 -11.5 20 1716G ¡ A AG 7/7 18.9 -20.1 IBD 21 1001 ϩ 11C/T AG 7/9 8.9 -13 22 S1235R/2752 - 26A ¡ G 185 ϩ 324C/T AG 7/7 15 -15 23 AG 7/7 17.8 -20 24 IVS8T5 AA 5/7 4.8 -10.4 25 875 ϩ 40A/G, 125G/C GG 7/7 10.8 -30 26 AG 7/7 22.9 -10.5 27 IVS8T5 AG 5/7 15.1 NP 28 AG 7/7 20.1 -8 29 R75Q GG 7/7 10.1 -17 30 AA 7/7 14 NP 31 Q1352H 4521A(hom), 4700T8/8 AG 7/7 3.5 -35 32 AA 7/7 11.8 -8 33 125G/C AG 7/7 9.4 -33 34 R75Q/IVS8T5 1898 ϩ 152T/A AG 5/7 4 -14 Subjects with IBD were disease control subjects. Login to comment

[hide] Cystic fibrosis transmembrane conductance regulato... Int J Urol. 2008 Mar;15(3):270-1. Sakamoto H, Yajima T, Suzuki K, Ogawa Y
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation associated with a congenital bilateral absence of vas deferens.
Int J Urol. 2008 Mar;15(3):270-1., [PMID:18304229]

Abstract [show]
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations associated with cystic fibrosis have been reported to be rare in Japanese patients with congenital bilateral absence of vas deferens (CBAVD). A 28-year-old Japanese male was referred for infertility. Vas deferens and epididymis were not palpable bilaterally. Semen analyses showed azoospermia with volumes below 2.0 ml. Serum follicle-stimulating hormone value was slightly elevated. Seminal fructose concentration was also very low. Scrotal ultrasonography showed absence of the bodies and tails of the right and left epididymides. Imaging studies showed cystic dysplasia of the right seminal vesicle and agenesis of the left seminal vesicle. A CFTR gene mutation of I556V was found. Recent studies show that prevalence of CFTR gene mutation in Japanese CBAVD patients may be approximately equal to that of the Caucasian population. Genetic counselling may be recommended for any couple attempting assisted reproduction technology when the man has CBAVD.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
28 Anzai et al. showed, using polymerase chain reaction (PCR) amplification single-strand confirmation polymorphism analysis and direct sequencing to analyze all 27 exons of the CFTR gene in 19 Japanese CBAVD patients, that three rare CFTR gene mutations (W216X, G1349S, Q1352H) were found in seven CFTR alleles of five patients, and IVS8-5T was positive in 11 alleles of 11 patients.2 Namely, 58% of the 19 CBAVD patients had at least one mutated CFTR allele.2 Moreover, three (5.7%) of 53 normal individuals had a missense mutation in one of their CFTR genes (E217G in 1, and Q1352H in 2).2 CFTR gene mutations may be frequently associated with Japanese CBAVD patients. Login to comment

[hide] Independent contribution of common CFTR variants t... Pancreas. 2010 Mar;39(2):209-15. de Cid R, Ramos MD, Aparisi L, Garcia C, Mora J, Estivill X, Farre A, Casals T
Independent contribution of common CFTR variants to chronic pancreatitis.
Pancreas. 2010 Mar;39(2):209-15., [PMID:19812525]

Abstract [show]
OBJECTIVE: We have assessed whether CFTR gene has a major impact on chronic pancreatitis (CP) pathogenesis than that provided by the CFTR mutations. For this aim, we have evaluated clinical parameters, CFTR mutations, and 3 potential regulatory CFTR variants (coding single-nucleotide polymorphisms): c.1540A>G, c.2694T>G, and c.4521G>A. METHODS: CFTR gene analysis was performed in a cohort of 136 CP patients and 93 controls from Spanish population using current scanning techniques (single-strand conformation polymorphism/heteroduplex, denaturing gradient gel electrophoresis, and denaturing high-performance liquid chromatography) and direct sequencing. RESULTS: A higher frequency of CFTR mutations were observed in patients (39%) than in controls (15%; P < or = 0.001), differences being mostly attributable to the prevalence of the cystic fibrosis (CF)-causing mutations (P = 0.009). The analysis of variants has shown statistically significant differences between patients and controls for c.4521G>A (Pcorrected = 0.036). Furthermore, the multi-marker analysis revealed that the 1540A;2694G;4521A (AGA) haplotype was more prevalent in CP than controls (Pcorrected = 0.042). Remarkably, this association was unrelated to CF-causing mutations (P = 0.006). CONCLUSIONS: Our results corroborate the higher susceptibility of CF carriers to CP and, furthermore, suggest that the AGA haplotype could contribute to an increased risk in the development of CP irrespective of other CF-causing mutations.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
38 Scanning Methodology Applied in CFTR Gene Analysis Amplicon Name Fragment Size, bp Control Set (n = 93) Patient Set 1 (n = 68) Patient Set 2 (n = 68) Control Sequence Exon 1 192 SSCP/HD SSCP/HD dHPLC 125G9C Exon 2 334 SSCP/HD SSCP/HD dHPLC 296+3insT Exon 3 309 DGGE DGGE dHPLC G85V Exon 4 436 SSCP/HD SSCP/HD dHPLC R117H Exon 5 466 DGGE DGGE dHPLC R170H Exon 6a 345 SSCP/HD SSCP/HD dHPLC L206W Exon 6b 331 SSCP/HD SSCP/HD SSCP/HD TTGA 6/7 Exon 7 410 SSCP/HD SSCP/HD dHPLC R334W Exon 8 328 DGGE DGGE dHPLC 1341+28C9T Exon 9 375 DGGE DGGE DGGE 7T/9T Exon 10 493 SSCP/HD SSCP/HD SSCP/HD F508del; 1540A/A Exon 11 322 DGGE DGGE dHPLC S549R Exon 12 426 DGGE DGGE dHPLC G576A Exon 13a 532 SSCP/HD SSCP/HD dHPLC R668C Exon 13b 498 SSCP/HD SSCP/HD dHPLC I807M Exon 14a 284 DGGE DGGE DGGE 2694T9G Exon 14b 211 DGGE DGGE dHPLC 2789+5G9A Exon 15 487 DGGE DGGE dHPLC D924N Exon 16 294 SSCP/HD SSCP/HD dHPLC 3041-71G9C Exon 17a 294 SSCP/HD SSCP/HD dHPLC L997F Exon 17b 463 DGGE DGGE dHPLC 3272-26A9G Exon 18 451 DGGE DGGE dHPLC N1148K Exon 19 588 SSCP/HD SSCP/HD SSCP/HD 3601-65C9A Exon 20 471 DGGE DGGE dHPLC W1282X Exon 21 477 DGGE DGGE DGGE 4029G9A Exon 22 339 SSCP/HD SSCP/HD dHPLC Q1352H Exon 23 249 DGGE DGGE dHPLC 4374+13A9G Exon 24 362 SSCP/HD SSCP/HD SSCP/HD 4521G9A Control set, general population series analyzed; patient set 1, previous patient series reported in 2004; and patient set 2, new patient series analyzed in this study. Login to comment

[hide] Cystic fibrosis transmembrane conductance regulato... Reprod Biomed Online. 2009 Nov;19(5):685-94. Gallati S, Hess S, Galie-Wunder D, Berger-Menz E, Bohlen D
Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners.
Reprod Biomed Online. 2009 Nov;19(5):685-94., [PMID:20021716]

Abstract [show]
The objective of this study was to investigate the contribution of cystic fibrosis transmembrane conductance regulator (CFTR) to human infertility and to define screening and counselling procedures for couples asking for assisted reproduction treatment. Extended CFTR mutation screening was performed in 310 infertile men (25 with congenital absence of the vas deferens (CAVD), 116 with non-CAVD azoospermia, 169 with severe oligospermia), 70 female partners and 96 healthy controls. CFTR mutations were detected in the majority (68%) of CAVD patients and in significant proportions in azoospermic (31%) and oligospermic (22%) men. Carrier frequency among partners of infertile men was 16/70, exceeding that of controls (6/96) significantly (P = 0.0005). Thus, in 23% of infertile couples both partners were carriers, increasing the risk for their offspring to inherit two mutations to 25% or 50%. This study emphasizes the necessity to offer extended CFTR mutation screening and counselling not only to patients with CAVD but also to azoospermic and oligozoospermic men and their partners before undergoing assisted reproduction techniques. The identification of rare and/or mild mutations will not be a reason to abstain from parenthood, but will allow adequate treatment in children at risk for atypical or mild cystic fibrosis as soon as they develop any symptoms.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
81 In 70 women whose partners had tested positive for either CFTR mutations or 5T alleles, extended screening of the CFTR gene was also performed revealing a mutation spectrum similar to that of oligospermic men including four 5T alleles, three S1235R, three F508del and one I148T, V754M, V920M, D1152H, 3905insT and Q1352H each (Table 1). Login to comment
99 Couple no. Infertile male CFTR mutation Female partner CFTR mutation Offspring genotype Risk for genotype (%) 01 F508del/wt azoospermia F508del/wt F508del/ F508del 25 F508del/wt 50 wt/wt 25 02 F508del/T5 CAVD F508del/wt F508del/ F508del 25 F508del/T5 25 F508del/wt 25 T5/wt 25 03 F508del/S13Ya azoospermia T5/wt F508del/T5 25 S13Y/T5 25 F508del/wt 25 S13Y/wt 25 04 I148T/wt oligospermia F508del/wt F508del/ I148T 25 I148T/wt 25 F508del/wt 25 wt/wt 25 05 1717À1G>A/wt oligospermia T5/wt 1717À1G>A/ T5 25 1717À1G>A/ wt 25 T5/wt 25 wt/wt 25 06 T5/wt oligospermia 3905insT/wt 3905insT/T5 25 3905insT/wt 25 T5/wt 25 wt/wt 25 07 T5/wt azoospermia D1152H/wt D1152H/T5 25 D1152H/wt 25 T5/wt 25 wt/wt 25 08 T5/F1052V oligospermia S1235R/wt F1052V/ S1235R 25 S1235R/T5 25 F1052V/wt 25 T5/wt 25 09 S1235R/wt oligospermia T5/wt S1235R/T5 25 S1235R/wt 25 T5/wt 25 wt/wt 25 10, 11 T5/wt oligospermia S1235R/wt S1235R/T5 25 S1235R/wt 25 T5/wt 25 wt/wt 25 12 V754M/wt oligospermia T5/wt V754M/T5 25 V754M/wt 25 T5/wt 25 wt/wt 25 13 T5/wt oligospermia Q1352H/wt Q1352H/T5 25 Q1352H/wt 25 T5/wt 25 wt/wt 25 (continued on next page)(continued) female partner is a carrier. Login to comment

[hide] The L441P mutation of cystic fibrosis transmembran... J Korean Med Sci. 2010 Jan;25(1):166-71. Epub 2009 Dec 26. Gee HY, Kim CK, Kim SW, Lee JH, Kim JH, Kim KH, Lee MG
The L441P mutation of cystic fibrosis transmembrane conductance regulator and its molecular pathogenic mechanisms in a Korean patient with cystic fibrosis.
J Korean Med Sci. 2010 Jan;25(1):166-71. Epub 2009 Dec 26., [PMID:20052366]

Abstract [show]
Cystic fibrosis (CF) is an autosomal recessive disorder usually found in populations of white Caucasian descent. CF is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. A 5-yr-old Korean girl was admitted complaining of coughing and greenish sputum. Chest radiographs and computed tomographic (CT) scan revealed diffuse bronchiectasis in both lungs. The patient had chronic diarrhea and poor weight gain, and the abdominal pancreaticobiliary CT scan revealed atrophy of the pancreas. Finally, CF was confirmed by the repeated analysis of the quantitative pilocarpine iontophoresis test. The chloride concentration of sweat samples taken from both forearms of the pateint was an average of 88.7 mM/L (normal value <40 mM/L). After a comprehensive search for mutations in the CFTR gene, the patient was found to carry the non-synonymous L441P mutation in one allele. Molecular physiologic analysis of the L441P mutation of CFTR revealed that the L441P mutation completely abolished the CFTR Cl(-) channel activity by disrupting proper protein folding and membrane trafficking of CFTR protein. These results confirmed the pathogenicity of the L441P mutation of CFTR circulating in the Korean population. The possibility of CF should be suspected in patients with chronic bronchiectasis, although the frequency of CF is relatively rare in East Asia.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
115 Some of them, especially E117G and Q1352H, showed an association with the monosymptomatic bronchiectasis or chronic pancreatitis. Login to comment
141 The heterozygote frequency of mild mutations, such as E217G and Q1352H, was estimated to 0.51% in the Korean population. Login to comment

[hide] Distribution of CFTR variations in an Indonesian e... Clin Infect Dis. 2010 May 1;50(9):1231-7. van de Vosse E, de Visser AW, Al-Attar S, Vossen R, Ali S, van Dissel JT
Distribution of CFTR variations in an Indonesian enteric fever cohort.
Clin Infect Dis. 2010 May 1;50(9):1231-7., 2010-05-01 [PMID:20233062]

Abstract [show]
BACKGROUND: Enteric fever is defined by circulating Salmonella serotype Typhi or Paratyphi in the blood. The first step in developing enteric fever is internalization of salmonellae in the gut epithelium. In in vitro experiments, attachment of S. Typhi to the cystic fibrosis transmembrane conductance regulator (CFTR) on the intestinal mucosa is crucial for bacterial uptake. We recently found a microsatellite polymorphism in the CFTR gene, IVS8CA, to be associated with susceptibility to enteric fever in a case-control study in Indonesia. METHODS: To determine which functional variation in CFTR is associated with susceptibility to enteric fever, we sequenced all 27 exons of the CFTR gene in 25 individuals from Indonesia. Polymorphisms that occurred more than once were genotyped in the full enteric fever cohort of 116 case patients and 322 control subjects. RESULTS: We identified 12 variants in, or adjacent to, the exons: 1 novel variant (L435V), 3 known mutations (N287K, I556V, Q1352H), and 8 known polymorphisms. Variations that occurred more than once were genotyped in the full cohort. The IVS8 TG(11)TG(12) genotype appears to provide some protection from acquiring enteric fever: having this protective genotype or a variation that is known to affect CFTR protein expression provides modest protection from enteric fever (odds ratio, 0.57; 95% confidence interval, 0.37-0.87; P<.01). CONCLUSIONS: The findings demonstrate that a correlation exists between variations in the CFTR gene and protection from enteric fever. The IVS8CA polymorphism that was identified previously may, however, be the principal functional variation causing the difference in susceptibility.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
8 We identified 12 variants in, or adjacent to, the exons: 1 novel variant (L435V), 3 known mutations (N287K, I556V, Q1352H), and 8 known polymorphisms. Login to comment
97 (%) 2-sided P value Of case patients (n p 116) Of control subjects (n p 322) IVS6a GATTn repeat at 9 nt before exon 6b; rs3034763 .40b GATT7 128 (57.1) 379 (60.4) GATT6 96 (42.9) 248 (39.5) GATT4 0 1 (0.2) IVS8 TGn repeat at 16 nt before exon 9; rs4646205 .17 c TG10 7 (3.0) 7 (1.2) TG11 110 (47.8) 298 (50.0) TG12 113 (49.1) 285 (47.8) TG13 0 (0) 5 (0.8) TG15 0 (0) 1 (0.2) IVS8 Tn repeat at 6 nt before exon 9; rs1805177 NDd T5 1 (0.4) 8 (1.3) T7 222 (96.5) 581 (97.5) T9 7 (3.0) 7 (1.2) 1408G1A in exon 10 leading to V470M; rs213950 .36 G 126 (56.3) 380 (59.7) A 98 (43.8) 256 (40.3) 2562T1G in exon 14a, silent; rs1042077 .78 T 138 (60.0) 392 (61.1) G 92 (40.0) 250 (38.9) 4056G1C in exon 22, leading to Q1352H; NA .56 G 220 (94.8) 602 (93.8) C 12 (5.2) 40 (6.2) 4389G1A in exon 24, silent; rs1800136 ND d G 220 (94.8) 617 (96.1) A 12 (5.2) 25 (3.9) NOTE. NA, not available; ND, not determined; SNP, single-nucleotide polymorphism. Login to comment
107 The 7 polymorphisms that were detected more frequently were a IVS6a GATT repeat polymorphism 9 base pairs (bp) upstream of exon 6b, a variation in the number of TG repeats 16 bp upstream of exon 9, an adjacent variation in the number of Ts 6 bp upstream of exon 9, the common 1408G1A coding single-nucleotide polymorphism (SNP) (leading to V470M), the silent SNP 2562T1G, the 4056G1C mutation (leading to Q1352H), and the silent SNP 4389G1A (Table 3). Login to comment
116 (%) 2-sided P value Of case patients (n p 116) Of control subjects (n p 322) IVS6a GATTn .59a GATT6GATT6 23 (20.5) 51 (16.2) GATT6GATT7 50 (44.6) 146 (46.5) GATT7GATT7 39 (34.8) 116 (36.9) GATT4GATT7 0 (0) 1 (0.3) IVS8 TGn .04b TG11TG11 31 (27.0) 72 (24.2) TG11TG12 45 (39.1) 150 (50.3) TG12TG12 32 (27.8) 64 (21.5) Other 7 (6.1) 12 (4.0) IVS8 Tn .45b T7T7 107 (93.0) 283 (95.0) T7T9 7 (6.1) 7 (2.3) Other 1 (0.9) 8 (2.7) 1408G1A (V470M) .55 GG 39 (34.8) 118 (37.1) GA 48 (42.9) 144 (45.3) AA 25 (22.3) 56 (17.6) 2562T1G .06 b TT 49 (42.6) 124 (38.6) TG 40 (34.8) 144 (44.9) GG 26 (22.6) 53 (16.5) 4056G1C (Q1352H) .44b GG 105 (90.5) 282 (87.9) GC 10 (8.6) 38 (11.8) CC 1 (0.9) 1 (0.3) 4389G1A .39 GG 104 (89.7) 296 (92.2) GA 12 (10.3) 25 (7.8) AA 0 (0) 0 (0) a GATT4GATT7 genotype arbitrarily grouped with GATT7GATT7. Login to comment
119 Bar graph comparing individuals who have у1 of the CFTR expression-affecting variations (the mutation Q1352H, the IVS8 TGn repeat alleles TG13 or TG15, the IVS8 Tn repeat allele T5, or 1 of the common genotypes [IVS8 TG11TG12 or 2562TG] that we found to protect from enteric fever) with individuals who have none of these variations. Login to comment
125 Several CFTR variations have been proven to affect CFTR protein function and expression directly (Q1352H) or are known to affect CFTR messenger RNA (mRNA) splicing (IVS8 TGn alleles TG13 and TG15 and the Tn repeat allele T5) and subsequent protein expression. Login to comment
126 In 63 case patients and 218 control subjects, у1 of the following variations were present: the Q1352H mutation, the IVS8 T5 allele, the IVS8 TG13 or TG15 allele, the most common TGn repeat genotype TG11TG12, or the most common 2562T1G genotype TG. Login to comment
145 Another example is the mutation in exon 22 that leads to the amino acid change Q1352H; this variation was identified in Korean, Japanese, and Singapore Chinese individuals [11, 28, 21] and was proven molecularly to be defective, and expression was reduced by 75% [11]. Login to comment
146 In Korean individuals, Q1352H was associated with pancreatitis and bronchiectasis [11], whereas in Japan it was found in several patients with CBAVD [28]. Login to comment

[hide] Genetic testing in pancreatitis. Gastroenterology. 2010 Jun;138(7):2202-6, 2206.e1. Epub 2010 Apr 20. Ooi CY, Gonska T, Durie PR, Freedman SD
Genetic testing in pancreatitis.
Gastroenterology. 2010 Jun;138(7):2202-6, 2206.e1. Epub 2010 Apr 20., [PMID:20416310]

Abstract [show]

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
53 Interpretation of Mutations Requires an Understanding of Their Functional Consequences Mutation group Reported mutations Complex allele: These mutations are recognized to occur on a single allele R117H ϩ T G576A ϩ R668C F508del ϩ I1027T Benign sequence alterations: These mutations have no known clinical consequence R74Q R297Q R74W 621 * 25 AϾG 3500-19 CϾT T164S C855I I1139V CFTR-related disorder associated: These mutations have been described in individuals with CF-like single organ disease (such as pancreatitis, sinopulmonary disease, or obstructive azoospermia), but do not fulfill the diagnostic criteria for CF 5T R117H D1270N L320V Q1352H 1818-18 GϾA S1235R CF causing F508del Q1476X R553X K710X G542X G551D F311L 2789-5 GϾA 2183AAϾG 711ϩ3 AϾG 3849ϩ10kb CϾT 1341ϩ1GϾA D1152Ha F1074La R553X Unknown clinical consequence F575Y L1260P G194R G1069R L997F K598E F834L R785Q To illustrate this point, mutations identified by extensive mutation testing in a cohort of patients with recurrent acute or chronic pancre- atitis14 are listed according to their clinical consequences (based on current consensus guidelines13 and functional and/or clinical reports; available: http://www.genet.sickkids.on.ca). Login to comment

[hide] Notable contribution of large CFTR gene rearrangem... Eur J Hum Genet. 2010 Oct;18(10):1166-9. Epub 2010 May 26. de Becdelievre A, Costa C, LeFloch A, Legendre M, Jouannic JM, Vigneron J, Bresson JL, Gobin S, Martin J, Goossens M, Girodon E
Notable contribution of large CFTR gene rearrangements to the diagnosis of cystic fibrosis in fetuses with bowel anomalies.
Eur J Hum Genet. 2010 Oct;18(10):1166-9. Epub 2010 May 26., [PMID:20512161]

Abstract [show]
Grade III fetal bowel hyperechogenicity and/or loop dilatation observed at the second trimester of pregnancy can be due to several disease conditions, including cystic fibrosis (CF). Screening for frequent CF mutations is performed as a first step and, in certain situations, such as when a frequent CF mutation is found in the fetus, the increased risk of CF justifies an in-depth study of the second allele. To determine the contribution of large CFTR gene rearrangements in such cases, detected using a semiquantitative fluorescent multiplex PCR (QFM-PCR) assay, we collated data on 669 referrals related to suspicion of CF in fetuses from 1998 to 2009. Deletions were found in 5/70 cases in which QFM-PCR was applied, dele19, dele22_23, dele2_6b, dele14b_15 and dele6a_6b, of which the last three remain undescribed. In 3/5 cases, hyperechogenicity was associated with dilatation and/or gallbladder anomalies. Of the total cases of CF recognized in the subgroup of first-hand referrals, deletions represent 16.7% of CF alleles. Our study thus strengthens the need to consider large CFTR gene rearrangements in the diagnosis strategy of fetal bowel anomalies, in particular in the presence of multiple anomalies.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
48 Table 1 Reasons of screening for large rearrangements In group 1 (first-hand referrals): 17/450 First step of the study: one CF mutation identified (n¼8) F508del (n¼6), 394delTT (n¼1), Q1352H (n¼1) Abnormal AF-DE (n¼4) Consanguinity in the couple (n¼1) Very suggestive ultrasound signsa (n¼4) In group 2 (second-hand referrals): 53/219 First step of the study: one CF mutation identified in another laboratory (n¼45) F508del (n¼36), N1303K (n¼3), G542X (n¼2), G551D, R553X, W1282X, 3849+10kbC4T (n¼1 for each) Abnormal AF-DE (n¼1) Consanguinity in the couple and presence of the [R74W;V201M;D1270N] complex allele (n¼1) Very suggestive ultrasound signsa (n¼6) aVery suggestive ultrasound signs mean that several abnormal signs were associated and/or clinicians insisted on a comprehensive study of the CFTR gene. Login to comment

[hide] Association between cystic fibrosis transmembrane ... Yonsei Med J. 2010 Nov;51(6):912-7. Kim KW, Lee JH, Lee MG, Kim KH, Sohn MH, Kim KE
Association between cystic fibrosis transmembrane conductance regulator gene mutations and susceptibility for childhood asthma in Korea.
Yonsei Med J. 2010 Nov;51(6):912-7., [PMID:20879059]

Abstract [show]
PURPOSE: Classic cystic fibrosis is now known part of cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders. These include a wide spectrum, from multi-system disorders, such as cystic fibrosis, to mono-symptomatic conditions, such as chronic pancreatitis or congenital bilateral absence of the vas deferens. However, respiratory disease is considered typical for the multi system disorder, cystic fibrosis, and is the major cause of morbidity and mortality. The purpose of this study was to evaluate the potential effects of CFTR gene mutations in Korean children with asthma. MATERIALS AND METHODS: We selected 14 mutations identified in Korea and each of the 48 children with and without asthma were genotyped for the case-control study. RESULTS: No significant differences were found in genotype and allele frequencies of the 9 polymorphisms observed between the non-asthma and asthma groups. In a haplotype determination based on a Bayesian algorithm, 8 haplotypes were assembled in the 98 individuals tested. However, we also did not find any significant differences in haplotype frequencies between the non-asthma and asthma groups. CONCLUSION: We have concluded that this study did not show any evidence in support of providing that CFTR genetic variations significantly contribute to the susceptibility of asthma in Korean children.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
53 CFTR Genetic Variations Analyzed in This Study Name Nucleotide change Exon Consequence Reference - 8G / C G to C at 125 5` UTR sequence variation 9 Q98R A to G at 425 Exon 4 Gln to Arg at 98 8 I125T T to C at 506 Exon 4 Ile to Thr at 125 9 E217G A to G at 782 Exon 6a Glu to Gly at 217 9 Q220X C to T at 790 Exon 6a Gln to Stop at 220 7, 8 A309A C or G at 1059 Exon 7 Sequence variation 9 TG repeat TG10-13 IVS 8 Splicing 9 T repeat T5-9 IVS 8 Splicing 9 M470V A or G at 1540 Exon 10 Met to Val at 470 9 I556V A to G at 1798 Exon 11 Ile to Val at 556 9 T854T T to G at 2694 Exon 14a Sequence variation 9 Q1291X C to T at 4003 Exon 20 Gln to Stop at 1291 9 Q1352H G to C at 4188 Exon 22 Gln to His at 1352 9 R1453W C to T at 4489 Exon 24 Arg to Trp at 1453 9 CFTR,cysticfibrosistransmembraneconductanceregulator. Login to comment
69 Frequency of CFTR Genetic Variations in Non-Asthma and Asthma Group Variants Non-asthma (n) Asthma (n) p value* - 8G / C G / G 39 37 0.466 G / C 8 11 C / C 1 0 E217G A / A 48 46 0.247 A / G 0 2 M470V A / A 8 10 0.858 A / G 25 23 G / G 15 15 I556V A / A 42 45 0.276 A / G 4 3 T854T T / T 15 16 0.639 T / G 26 22 G / G 7 10 Q1352H G / G 46 46 0.383 G / C 2 2 R1453W C / C 47 46 0.500 C / T 0 1 Microsatellite TG repeat (IVS 8)� W / W� 10 12 0.119 W / M 27 18 M / M 10 18 T repeat (IVS 8) 5 / 7 2 1 0.141 6 / 7 0 1 7 / 7 44 42 7 / 9 1 4 CFTR,cysticfibrosistransmembraneconductanceregulator. Login to comment
75 However the background haplotype for ∆F508,27 which accounts for 66% of worldwide cystic fibrosis, is very rare in the Korean population.11 Besides, genetic variants at Q1352H or E217G were found to be associated with bronchiectasis and/or chronic pancreatitis in the Korean population.11 In particular, nonsynonymous Q1352H and E217G mutations in the M470 background caused a 60-80% reduction in CFTR-dependent Cl- currents and HCO3-transport activities. Login to comment

[hide] Heterogeneous spectrum of CFTR gene mutations in K... Korean J Lab Med. 2011 Jul;31(3):219-24. Epub 2011 Jun 28. Jung H, Ki CS, Koh WJ, Ahn KM, Lee SI, Kim JH, Ko JS, Seo JK, Cha SI, Lee ES, Kim JW
Heterogeneous spectrum of CFTR gene mutations in Korean patients with cystic fibrosis.
Korean J Lab Med. 2011 Jul;31(3):219-24. Epub 2011 Jun 28., [PMID:21779199]

Abstract [show]
BACKGROUND: Cystic fibrosis (CF) is one of the most common hereditary disorders among Caucasians. The most common mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been well established among Caucasian populations. In Koreans, however, there are very few cases of genetically confirmed CF thus far, and the spectrum of mutations seems quite different from that observed in Caucasians. METHODS: In the present study, we describe the cases of 2 Korean CF patients, present sequencing results identifying mutations in their CFTR gene, and summarize the results of CFTR mutational spectrum from previously reported Korean CF patients. The mutations described were identified by performing direct sequencing analysis of the complete coding regions and flanking intronic sequences of the CFTR gene, followed by multiplex ligation-dependent probe amplification (MLPA) analysis in order to detect gene deletions or duplications that could not be identified by a direct sequencing method. RESULTS: Three CFTR mutations were identified in the 2 patients, including p.Q98R, c.2052delA, and c.579+5G>A. In an analysis of 9 Korean CF patients that included the 2 patients presented in this study, p.Q98R mutation was the only recurrently observed mutation with a frequency of 18.8% (3/16 alleles). Furthermore, only one of the mutations (c.3272-26A>G) was found among the 32 common mutations in the screening panel for Caucasians from the Cystic Fibrosis Mutation Database. CONCLUSIONS: Sequencing of the entire CFTR gene followed by MLPA analysis, rather than using the targeted sequencing-based screening panel for mutations commonly found in Caucasian populations, is recommended for genetic analysis of Korean CF patients.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
89 Aminoacid change Exon Nucleotide number Nucleotide change Typeof mutation Method ofdetection Familialtargetedmutationstudy Ref Father Mother Brother Sister 1 Q98R Exon4 293 A>G Missense Sequencing ND - - NA Thisstudy L728NfsX38 Exon13 2,052 delA Frameshift Sequencing ND + + NA 2 IVS4 579+5 G>A Splicing Sequencing ND ND NA NA Thisstudy 3 Q98R Exon4 293 A>G Missense Sequencing + - + - [15] Q220X Exon6a 658 C>T Nonsense Sequencing - + - - 4 Q98R Exon4 293 A>G Missense Sequencing + - NA NA [16] Q1352H Exon24 4,056 G>C Missense Sequencing - + NA NA 5 IVS12 1,766+2 T>C Splicing Sequencing + - NA NA [18] N1303KfsX6 Exon21 3,908 dupA Frameshift Sequencing - + NA NA 6 IVS17a 3,272-26 A>G Splicing Sequencing MLPA ND ND NA NA [17] Exon14a 2,623-2,751+? Login to comment
81 The identified mutations included 3 missense mutations (p.Q98R, p.Q1352H, and p.L441P), 3 nonsense mutations (p.Q220X, p.Q1291X, and p.L88X), 1 duplication with frameshift (c.3908dupA), 1 insertion with frameshift (c.2089-2090insA), 4 splice site mutations (c.1766+2T>C, c.3272-26A>G, c.579+5G>A, and IVS8-T5) and 2 deletion mutations (c.2052delA and c.2623-?_2751+?del). Login to comment

[hide] Genetics and pathogenesis of chronic pancreatitis:... Clin Res Hepatol Gastroenterol. 2012 Aug;36(4):334-40. doi: 10.1016/j.clinre.2012.05.003. Epub 2012 Jun 30. Chen JM, Ferec C
Genetics and pathogenesis of chronic pancreatitis: the 2012 update.
Clin Res Hepatol Gastroenterol. 2012 Aug;36(4):334-40. doi: 10.1016/j.clinre.2012.05.003. Epub 2012 Jun 30., [PMID:22749696]

Abstract [show]
Chronic pancreatitis is a persistent inflammation of the pancreas that results in irreversible morphological changes and impairment of both exocrine and endocrine functions. Genetic studies of the disease over the past 15 years have led to the identification of four firmly established susceptibility genes namely PRSS1, SPNIK1, CTRC and CFTR. Our previously published review (Chen and Ferec. Annu Rev Genomics Hum Genet 2009) has comprehensively summarized the advances made in terms of genetics and pathogenesis of chronic pancreatitis, covering the data available up to early 2009. This review summarizes the important and representative findings published thereafter, focusing on (i) newly found disease-causing mutations, (ii) functional characterization of known variations and (iii) genotype and phenotype relationship.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
67 Missense mutation [first description] Occurrence Known co-inherited variant(s) Experimentally demonstrated functional consequence Pathogenic relevance Previously analyzed L12F [43] Common polymorphism - No significant loss of PSTI expression [43] No L14R [43] Rare - 20% of PSTI expression [43] Yes L14P [5] Rare - No PSTI expression [43] Yes N34S [73] Common polymorphism See text No significant loss of PSTI expression [42,44,48] See text G48E [42] Rare - No PSTI expression [42] Yes D50E [74] Rare - No PSTI expression [42,44] Yes Y54H [75] Rare - <5% of normal PSTI expression [42,44] Yes P55S [73] Common polymorphism - No significant loss of PSTI expression [42,44] No R65Q [76] Rare - 40% of normal PSTI expression[42,44] Yes R67C [77] Rare - Barely detectable PSTI expression [42,44] Yes Newly analyzed S10N [45] Rare - No significant loss of PSTI expression [45] No N37S [78] Rare SPINK1 N34S and CFTR Q1352H No significant loss of PSTI expression [45] No N64D [45] Rare - No PSTI expression [45] Yes K66N [78] Rare - No PSTI expression [45] Yes R67H [45] Rare - No PSTI expression [45] Yes Q68R [78] Rare PRSS1 N29I Significantly increased PSTI expression [45] See text T69I [79] Rare - No PSTI expression [45] Yes C79F [45] Rare - No PSTI expression [45] Yes -142T > C, -147A > G, -164G > C, -170G > A, -215G > A and -215G > T) was recently investigated by means of both luciferase reporter gene assay and electrophoretic mobility shift assay, using human pancreatic COLO-357 cells as an expression system. Login to comment

[hide] Mutations in the cystic fibrosis transmembrane con... J Cyst Fibros. 2012 Jul;11(4):316-23. doi: 10.1016/j.jcf.2012.01.005. Epub 2012 Apr 6. Li H, Wen Q, Li H, Zhao L, Zhang X, Wang J, Cheng L, Yang J, Chen S, Ma X, Wang B
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens.
J Cyst Fibros. 2012 Jul;11(4):316-23. doi: 10.1016/j.jcf.2012.01.005. Epub 2012 Apr 6., [PMID:22483971]

Abstract [show]
BACKGROUND: Genetic testing of the cystic fibrosis transmembrane conductance (CFTR) gene is currently performed in patients with congenital bilateral absence of vas deferens (CBAVD). This study was conducted to investigate the role of mutations in the CFTR gene in CBAVD-dependent male infertility. METHODS: 73 Chinese patients diagnosed with CBAVD were studied. The entire coding regions and splice sites of 27 exons of the CFTR gene were sequenced in 146 chromosomes from the 73 CBAVD patients. Screening was carried out using PCR, gel electrophoresis and DNA sequencing to identify novel variants of the entire coding regions and boundaries of the 27 exons. RESULTS: Five novel nonsynonymous mutations, three novel splice site mutations and one deletion were identified by sequencing. Apart from the novel variants, we also found 19 previously reported mutations and polymorphism sites. Thirty-four patients (46.57%) had the 5T variant (6 homozygous and 28 heterozygous) and in two of them it was not associated with any detectable mutation of the CFTR gene. All potential pathogenic mutations are not contained in the 1000 Genome Project database. In total, the present study identified 30 potential pathogenic variations in the CFTR gene, 9 of which had not previously been described. CONCLUSIONS: Most patients with CBAVD have mutations in the CFTR gene. A mild genotype with one or two mild or variable mutations was observed in all the patients. These findings improve our understanding of the distribution of CFTR alleles in CBAVD patients and will facilitate the development of more sensitive CFTR mutation screening.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
77 Lastly, we have observed previously reported mutations and polymorphisms (p.E217G, p.R347H, p.V470M, p.R553X, p.I556V, p.T854T, p.G970D, p.P1290P, p.Q1352H, p.Q1643Q, 744-5delGATT, IVS8-T5) (Supplementary Table 1). Login to comment
119 △F508 R117H Mutation genotypes IVS8-Tn n (%) Two mutations detected Neg Neg I556V/I556V 7T/7T 1(1.3) Neg Neg I556V/1209+2 G-C 5T/7T 1(1.3) Neg Neg I556V/726delATT 5T/5T 1(1.3) Neg Neg I556V/- 5T/5T 1(1.3) Neg Neg I556V/- 5T/7T 1(1.3) Neg Neg G970D/- 5T/7T 1(1.3) Neg Neg C592F/- 5T/5T 1(1.3) Neg Neg 1209+1 G-C/- 5T/7T 1(1.3) Neg Neg R553X/- 5T/7T 1(1.3) Neg Neg Q1352H/- 5T/7T 1(1.3) Neg Neg S485C/- 5T/7T 1(1.3) Neg Neg A357T/- 5T/7T 1(1.3) Neg Neg E217G/- 5T/7T 1(1.3) Neg Neg R347H/- 5T/7T 1(1.3) Neg Neg G451K/- 5T/7T 1(1.3) Neg Neg L558S/- 5T/7T 1(1.3) Neg Neg 3635delT/Q1352H 7T/7T 1(1.3) Neg Neg A1136T/G970D 7T/7T 1(1.3) Neg Neg 870-1 G-C/- 5T/7T 1(1.3) Neg Neg 520-2 A-G/- 5T/7T 1(1.3) Neg Neg R419I/- 5T/7T 1(1.3) Neg Neg C491F/Q1643Q 7T/7T 1(1.3) Neg Neg Q1352H/- 5T/7T 1(1.3) Neg Neg R851X/- 5T/7T 1(1.3) Neg Neg P750L/G970D 7T/7T 1(1.3) One mutation detected Neg Neg -/- 5T/7T 2(2.7) Neg Neg -/- 5T/7T 3(4.1) Neg Neg -/- 5T/7T 5(6.8) Neg Neg -/- 5T/5T 2(2.7) Neg Neg -/- 5T/5T 1(1.3) Neg Neg G970D/- 7T/7T 2(2.7) Neg Neg D993Y/- 7T/7T 1(1.3) Neg Neg I556V/- 7T/7T 1(1.3) Neg Neg T388R/- 7T/7T 1(1.3) No mutation detected Neg Neg -/- 7T/7T 8(10.9) Neg Neg -/- 7T/7T 15(20.5) Neg Neg -/- 7T/9T 2(2.7) Neg Neg -/- 7T/7T 4(5.5) Neg: Negative. Login to comment
76 Lastly, we have observed previously reported mutations and polymorphisms (p.E217G, p.R347H, p.V470M, p.R553X, p.I556V, p.T854T, p.G970D, p.P1290P, p.Q1352H, p.Q1643Q, 744-5delGATT, IVS8-T5) (Supplementary Table 1). Login to comment
118 b3;F508 R117H Mutation genotypes IVS8-Tn n (%) Two mutations detected Neg Neg I556V/I556V 7T/7T 1(1.3) Neg Neg I556V/1209+2 G-C 5T/7T 1(1.3) Neg Neg I556V/726delATT 5T/5T 1(1.3) Neg Neg I556V/- 5T/5T 1(1.3) Neg Neg I556V/- 5T/7T 1(1.3) Neg Neg G970D/- 5T/7T 1(1.3) Neg Neg C592F/- 5T/5T 1(1.3) Neg Neg 1209+1 G-C/- 5T/7T 1(1.3) Neg Neg R553X/- 5T/7T 1(1.3) Neg Neg Q1352H/- 5T/7T 1(1.3) Neg Neg S485C/- 5T/7T 1(1.3) Neg Neg A357T/- 5T/7T 1(1.3) Neg Neg E217G/- 5T/7T 1(1.3) Neg Neg R347H/- 5T/7T 1(1.3) Neg Neg G451K/- 5T/7T 1(1.3) Neg Neg L558S/- 5T/7T 1(1.3) Neg Neg 3635delT/Q1352H 7T/7T 1(1.3) Neg Neg A1136T/G970D 7T/7T 1(1.3) Neg Neg 870-1 G-C/- 5T/7T 1(1.3) Neg Neg 520-2 A-G/- 5T/7T 1(1.3) Neg Neg R419I/- 5T/7T 1(1.3) Neg Neg C491F/Q1643Q 7T/7T 1(1.3) Neg Neg Q1352H/- 5T/7T 1(1.3) Neg Neg R851X/- 5T/7T 1(1.3) Neg Neg P750L/G970D 7T/7T 1(1.3) One mutation detected Neg Neg -/- 5T/7T 2(2.7) Neg Neg -/- 5T/7T 3(4.1) Neg Neg -/- 5T/7T 5(6.8) Neg Neg -/- 5T/5T 2(2.7) Neg Neg -/- 5T/5T 1(1.3) Neg Neg G970D/- 7T/7T 2(2.7) Neg Neg D993Y/- 7T/7T 1(1.3) Neg Neg I556V/- 7T/7T 1(1.3) Neg Neg T388R/- 7T/7T 1(1.3) No mutation detected Neg Neg -/- 7T/7T 8(10.9) Neg Neg -/- 7T/7T 15(20.5) Neg Neg -/- 7T/9T 2(2.7) Neg Neg -/- 7T/7T 4(5.5) Neg: Negative. Login to comment

[hide] Chronic pancreatitis in India and Asia. Curr Gastroenterol Rep. 2012 Apr;14(2):118-24. Garg PK
Chronic pancreatitis in India and Asia.
Curr Gastroenterol Rep. 2012 Apr;14(2):118-24., [PMID:22327961]

Abstract [show]
Chronic pancreatitis (CP) is widely prevalent in Asian countries much more so in India and Japan. The phenotype of CP is somewhat similar to that reported from western countries. The prevalent types of CP are mainly idiopathic and alcohol related. Current evidence suggests that the term "tropical pancreatitis" used for idiopathic CP from India is a misnomer. Gallstones' association with CP reported from China remains controversial. There has been ample evidence that mutations in the SPNIK1 and CFTR genes are strongly associated with idiopathic CP in patients from different ethnic backgrounds. Oxidative stress is important in the pathophysiology and antioxidants have been shown to result in significant pain relief with CP. Home-made balanced diet is effective for treating malnutrition in patients with CP. Endoscopic therapy combined with ESWL may provide significant relief in patients with pancreatic ductal calculi/stricture. Surgery is quite effective in CP and may be better than endotherapy.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
107 In an earlier Japanese study of 65 patients with CP, a high association of Q1352H (12.3% vs. 3.7% in controls) and R1453W (6.2% vs. 3.1%) mutations in the CFTR gene were found although CF is reportedly rare in Japan [39]. Login to comment
122 In the CFTR gene, haplotype 4 containing Q1352H showed the strongest association with CP (p00.008) in a Korean study [47]. Login to comment
108 In an earlier Japanese study of 65 patients with CP, a high association of Q1352H (12.3% vs. 3.7% in controls) and R1453W (6.2% vs. 3.1%) mutations in the CFTR gene were found although CF is reportedly rare in Japan [39]. Login to comment
123 In the CFTR gene, haplotype 4 containing Q1352H showed the strongest association with CP (p00.008) in a Korean study [47]. Login to comment

[hide] Novel strategies in newborn screening for cystic f... Thorax. 2012 Apr;67(4):289-95. Epub 2012 Jan 23. Vernooij-van Langen AM, Loeber JG, Elvers B, Triepels RH, Gille JJ, Van der Ploeg CP, Reijntjens S, Dompeling E, Dankert-Roelse JE
Novel strategies in newborn screening for cystic fibrosis: a prospective controlled study.
Thorax. 2012 Apr;67(4):289-95. Epub 2012 Jan 23., [PMID:22271776]

Abstract [show]
CONTEXT: Newborn screening for cystic fibrosis (CF) is included in many routine programmes but current strategies have considerable drawbacks, such as false-positive tests, equivocal diagnosis and detection of carriers. OBJECTIVE: To assess the test performance of two newborn screening strategies for CF. DESIGN, SETTING AND PARTICIPANTS: In 2008 and 2009, CF screening was added to the routine screening programme as a prospective study in part of The Netherlands. INTERVENTIONS: Two strategies were performed in all newborns. In the first strategy, concentrations of immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP) were measured. In the second method, samples with IRT >/=60 mug/litre were analysed for 36 CFTR mutations, followed by sequencing when a single mutation was detected. Tests were positive only with two identified CFTR mutations. MAIN OUTCOME: Sensitivity, specificity and positive predictive value (PPV) of both screening strategies. RESULTS: 145,499 infants were screened. The IRT/PAP approach showed a sensitivity of 95.0%, a specificity of 99.897% and a PPV of 12.3%. Test properties for the IRT/DNA/sequencing strategy were respectively 100%, 100% and 64.9%. Combining both strategies (IRT/PAP/DNA/sequencing) led to a sensitivity of 95.0%, a specificity of 100% and a PPV of 87.5%. CONCLUSION: In conclusion, all strategies performed well. Although there was no statistically significant difference in test performance, the IRT/DNA/sequencing strategy detected one infant that was missed by IRT/PAP (/DNA/sequencing). IRT/PAP may be the optimal choice if the use of DNA technology must be avoided. If identification of carriers and equivocal diagnosis is considered an important disadvantage, IRT/PAP/DNA/sequencing may be the best choice.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
105 Three of these infants had equivocal sweat test results (chloride 33, 34, 36 mmol/litre; all had R117H-7T as a second mutation), the other 10 had normal sweat tests (F508del/394delTT/ S1251N/R553X combined with R117H-7T n¼8, F508del/L967S, F508del/Q1352H) (table 3). Login to comment
136 CF, cystic fibrosis; IRT, immunoreactive trypsinogen; PAP, pancreatitis-associated protein. Table 3 Immunoreactive trypsinogen and pancreatitis-associated protein concentrations, CFTR gene mutation analysis and sweat tests for all infants with an equivocal diagnosis IRT (mg/litre) PAP (mg/litre) Mutation 1 Mutation 2 Sweat test chloride (mmol/litre) 1 199 1.4 E60X R117H-7T 36 2 139 0.8 394delTT R117H-7T/9T 21 3 123 0.6 F508del R117H-7T 22 4 89 1.4 S1251N R117H-7T 29 5 79 1.6 F508del R117H-7T 26 6 77 2.4 R553X R117H-7T 22 7 76 0.8 F508del R117H-7T 34 8 73 0.5 F508del R117H-7T 25 9 70 1.0 F508del R117H-7T 22 10 69 1.1 F508del R117H-7T 33 11 67 2.7 F508del R117H-7T 17 12* 174 3.8 F508del L967S 19 13* 84 3.2 F508del Q1352H 17 Equivocal diagnosis¼two CFTR gene mutations of which one has unclear clinical significance, and a normal or equivocal sweat test result. Login to comment
104 Three of these infants had equivocal sweat test results (chloride 33, 34, 36 mmol/litre; all had R117H-7T as a second mutation), the other 10 had normal sweat tests (F508del/394delTT/ S1251N/R553X combined with R117H-7T n&#bc;8, F508del/L967S, F508del/Q1352H) (table 3). Login to comment
135 CF, cystic fibrosis; IRT, immunoreactive trypsinogen; PAP, pancreatitis-associated protein. Table 3 Immunoreactive trypsinogen and pancreatitis-associated protein concentrations, CFTR gene mutation analysis and sweat tests for all infants with an equivocal diagnosis IRT (mg/litre) PAP (mg/litre) Mutation 1 Mutation 2 Sweat test chloride (mmol/litre) 1 199 1.4 E60X R117H-7T 36 2 139 0.8 394delTT R117H-7T/9T 21 3 123 0.6 F508del R117H-7T 22 4 89 1.4 S1251N R117H-7T 29 5 79 1.6 F508del R117H-7T 26 6 77 2.4 R553X R117H-7T 22 7 76 0.8 F508del R117H-7T 34 8 73 0.5 F508del R117H-7T 25 9 70 1.0 F508del R117H-7T 22 10 69 1.1 F508del R117H-7T 33 11 67 2.7 F508del R117H-7T 17 12* 174 3.8 F508del L967S 19 13* 84 3.2 F508del Q1352H 17 Equivocal diagnosis&#bc;two CFTR gene mutations of which one has unclear clinical significance, and a normal or equivocal sweat test result. Login to comment

[hide] Gene SNPs and mutations in clinical genetic testin... Mutat Res. 2005 Jun 3;573(1-2):195-204. Lee JE, Choi JH, Lee JH, Lee MG
Gene SNPs and mutations in clinical genetic testing: haplotype-based testing and analysis.
Mutat Res. 2005 Jun 3;573(1-2):195-204., [PMID:15829248]

Abstract [show]
Haplotype-based analysis using high-density single nucleotide polymorphism (SNP) markers have gained increasing attention in evaluating candidate genes in various clinical situations. For example, haplotype information is useful for predicting the severity and prognosis of certain genetic disorders. The intragenic cis-interactions between the common polymorphisms and the pathogenic mutations of prion protein (PRNP) and cystic fibrosis transmembrane conductance regulator (CFTR) genes greatly influence the phenotypes and the disease penetrance of hereditary Creutzfeldt-Jakob disease and cystic fibrosis. Merits of haplotype study are more evident in the fine mapping of complex diseases and in identifying genetic variations that influence individual's response to drugs. Knowledge-based approaches and/or linkage analyses using SNP tagged haplotypes are effective tools in detecting genetic associations. For example, haplotype studies in the inflammatory bowel disease susceptibility loci revealed diverse cis and trans gene-gene interactions, which can affect the clinical outcomes. Although currently, we have very limited knowledge on haplotype-phenotypic characterizations of most genes, these examples demonstrate that increased understanding of the clinically relevant haplotypes will provide better results in the diagnosis and possibly in the treatment of both monogenic and polygenic diseases.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
722 Interactions between M470V and Q1352H in human CFTR gene. Login to comment
726 M470V is located in NBD1 and Q1352H in NBD2. Login to comment
739 Recently, a couple of studies reported a high incidence of Q1352H mutation in chronic pancreatitis patients in Korea and Japan [22,29]. Login to comment
740 A haplotype reconstruction using the population genotype data revealed that the Q1352H mutation always arises in the V470 background. Login to comment
742 However, in the V470 background, the Q1352H mutation almost completely abolished the anion transporting activities, which explains the high disease association of this mutant in the real population [22] (Fig. 1B). Login to comment
744 The reasons for the complete reduction in the functional activities of V470-H1352 haplotype are unclear atthismoment.Aplausiblescenarioisthat,M470Vand Q1352H might be involved in the cross talk and/or interaction between the two nucleotide-binding domains (NBDs) of CFTR, because M470V and Q1352H are located in the NBD1 and NBD2, respectively (Fig. 1A). Login to comment
747 Therefore, on top of the NBD1 defect induced by M470V, an additional NBD2 defect of Q1352H would deteriorate the CFTR function even further. Login to comment
721 Interactions between M470V and Q1352H in human CFTR gene. Login to comment
725 M470V is located in NBD1 and Q1352H in NBD2. Login to comment
738 Recently, a couple of studies reported a high incidence of Q1352H mutation in chronic pancreatitis patients in Korea and Japan [22,29]. Login to comment
741 However, in the V470 background, the Q1352H mutation almost completely abolished the anion transporting activities, which explains the high disease association of this mutant in the real population [22] (Fig. 1B). Login to comment
743 The reasons for the complete reduction in the functional activities of V470-H1352 haplotype are unclear atthismoment.Aplausiblescenarioisthat,M470Vand Q1352H might be involved in the cross talk and/or interaction between the two nucleotide-binding domains (NBDs) of CFTR, because M470V and Q1352H are located in the NBD1 and NBD2, respectively (Fig. 1A). Login to comment
746 Therefore, on top of the NBD1 defect induced by M470V, an additional NBD2 defect of Q1352H would deteriorate the CFTR function even further. Login to comment

[hide] Distinct spectrum of CFTR gene mutations in congen... Hum Genet. 1997 Sep;100(3-4):365-77. Dork T, Dworniczak B, Aulehla-Scholz C, Wieczorek D, Bohm I, Mayerova A, Seydewitz HH, Nieschlag E, Meschede D, Horst J, Pander HJ, Sperling H, Ratjen F, Passarge E, Schmidtke J, Stuhrmann M
Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens.
Hum Genet. 1997 Sep;100(3-4):365-77., [PMID:9272157]

Abstract [show]
Congenital absence of the vas deferens (CAVD) is a frequent cause for obstructive azoospermia and accounts for 1%-2% of male infertility. A high incidence of mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has recently been reported in males with CAVD. We have investigated a cohort of 106 German patients with congenital bilateral or unilateral absence of the vas deferens for mutations in the coding region, flanking intron regions and promotor sequences of the CFTR gene. Of the CAVD patients, 75% carried CFTR mutations or disease-associated CFTR variants, such as the "5T" allele, on both chromosomes. The distribution of mutation genotypes clearly differed from that observed in cystic fibrosis. None of the CAVD patients was homozygous for delta F508 and none was compound heterozygous for delta F508 and a nonsense or frameshift mutation. Instead, homozygosity was found for a few mild missense or splicing mutations, and the majority of CAVD mutations were missense substitutions. Twenty-one German CAVD patients were compound heterozygous for delta F508 and R117H, which was the most frequent CAVD genotype in our study group. Haplotype analysis indicated a common origin for R117H in our population, whereas another frequent CAVD mutation, viz. the "5T allele" was a recurrent mutation on different intragenic haplotypes and multiple ethnic backgrounds. We identified a total of 46 different mutations and variants, of which 15 mutations have not previously been reported. Thirteen novel missense mutations and one unique amino-acid insertion may be confined to the CAVD phenotype. A few splice or missense variants, such as F508C or 1716 G-->A, are proposed here as possible candidate CAVD mutations with an apparently reduced penetrance. Clinical examination of patients with CFTR mutations on both chromosomes revealed elevated sweat chloride concentrations and discrete symptoms of respiratory disease in a subset of patients. Thus, our collaborative study shows that CAVD without renal malformation is a primary genital form of cystic fibrosis in the vast majority of German patients and links the particular expression of clinical symptoms in CAVD with a distinct subset of CFTR mutation genotypes.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
81 The R297W mutation was identified on a Q1352H chromosome in a Vietnamese CBAVD patient (see below). Login to comment
91 R. Knowles, Q1352H by T. Nukiwa and K. Seyama are indicated g Missense substitutions R933S and R75Q occurred together in a ∆F508 heterozygous patient h Q1352H is associated with 5T and R297W, respectively i Missense substiutions G576A and R668C are linked on the same allele in both CBAVD patients sence of the vas deferens (CUAVD) and one heterozygote with CBAVD. Login to comment
132 This male was homozygous for a missense mutation, Q1352H, in exon 22 of the CFTR gene, but heterozygous for a "5T" allele and for the novel R297W missense mutation. Login to comment
133 Missense mutation Q1352H, located in the ABC signature of the NBD2 of CFTR, has so far only been observed in the heterozygous state in 1 out of 18 Japanese patients with diffuse panbronchiolitis (K. Seyama, personal communication). Login to comment
134 The Q1352H mutation may be insufficient to cause CBAVD but the additional occurrence of one "5T" 370 Variant Allele frequency n (% of chromosomes) Random donors Non-CF CBAVD CF 125G→C 15/178 (8.5%) n.d. 2/212 (0.9%) 1/1000 (0.1%)a R75Q 4/188 (2.2%) 3/130 (2.1%) 2/212 (0.9%)b 1/1000 (0.1%) 5T 9/186 (4.8%) 2/65 (2.9%) 26/212 (12.3%)c 3/1000 (0.3%) F508C 0/188 n.d. 3/212 (1.4%) 2/1000 (0.2%)d 1716G→A 5/188 (2.6%) 3/212 (1.5%) 3/212 (1.4%) 2/1000 (0.2%)e G576A-R668C 0/188 n.d. 2/212 (0.9%)f 3/1000 (0.3%)f Table 2 Frequency distribution of CFTR variants in different subgroups of individuals. Login to comment
137 Complex alleles are indicated a One CF allele with R75X and 125G→C b One CBAVD allele with R75Q and R933S c One CBAVD allele with 5T and Q1352H d Two CF alleles with F508C and S1251N e One CF allele with 1716G→A and L619S f G576A and R668C were linked on two CBAVD and three CF alleles, whereas two additional CF alleles carried R668C together with the 3849+10kB C→T mutation (Dörk and Stuhrmann 1995) 371 Table 3 CFTR mutation genotypes in 106 males with CAVD Genotype PolyT Frequency Ethnic descent Diagnosis ∆F508/R117H 9/7 21 German, Austrian 20 CBAVD, 1 CUAVD ∆F508/5T 9/5 9 German, Austrian 8 CBAVD, 1 CUAVD ∆F508/F508C 9/7 3 German CBAVD ∆F508/R347H 9/9 2 German CBAVD ∆F508/1716 G→A 9/7 2 German CBAVD ∆F508/3272-26 A→G 9/7 2 German CBAVD ∆F508/E56K 9/7 1 German CBAVD ∆F508/M265R 9/7 1 German-Portuguese CBAVD ∆F508/R334W 9/9 1 German CBAVD ∆F508/T351S 9/9 1 German CBAVD ∆F508/L375F 9/7 1 Volga German CBAVD ∆F508/G576A & R668C 9/7 1 German CBAVD ∆F508/R933S 9/7 1 German CBAVD ∆F508/L997F 9/9 1 German CBAVD ∆F508/Y1032C 9/7 1 German CBAVD ∆F508/D1152H 9/7 1 German CBAVD ∆F508/K1351E 9/7 1 German CBAVD ∆F508/D1377H 9/7 1 Portuguese CBAVD ∆F508/L1388Q 9/7 1 German CBAVD ∆F508/unknown 9/7 4 German 3 CBAVD, 1 CUAVD 5T/5T 5/5 2 German CBAVD 5T/G542X 5/9 2 German, Turkish CBAVD 5T/D58N 5/7 1 Lebanese CBAVD 5T/̃L138 5/7 1 German-Polish CBAVD 5T/1078delT 5/7 1 German CBAVD 5T/R553X 5/7 1 German CBAVD 5T/2184insA 5/7 1 Turkish CBAVD 5T/D979A 5/7 1 Vietnamese CBAVD 5T/D1152H 5/7 1 Turkish CBAVD 5T/3659delC 5/7 1 German CBAVD 5T/S1235R 5/7 1 Greek CBAVD 5T/W1282X 5/7 1 German CBAVD 5T & Q1352H/ R297W & Q1352H 5/7 1 Vietnamese CBAVD 5T/unknown 5/7 1 German CBAVD R117H/L206W 7/9 1 German CBAVD R117H/2789+5 G→A 7/7 1 German CBAVD R117H/unknown 7/7 1 German CBAVD 2789+5 G→A/2789+5 G→A 7/7 1 Lebanese CBAVD 2789+5 G→A/L973F 7/7 1 German CBAVD V938G/V938G 7/7 1 Greek CBAVD V938G/174delA 7/7 1 German CBAVD D110H/D110H 7/7 1 Turkish CBAVD R334L/I336K 7/7 1 German CBAVD R347H/N1303K 9/9 1 German CBAVD L568F/D1152H 7/7 1 Turkish CBAVD 3272-26 A→G/V1153E 7/7 1 German CBAVD R75Q/unknown 7/7 1 German CBAVD A120T/unknown 9/7 1 German CBAVD 1716G→A/unknown 7/7 1 German CBAVD G576A & R668C/unknown 7/7 1 German CBAVD 2752-15 C→G/unknown 7/7 1 Iranian CBAVD Unknown/unknown 17 German, Turkish 7 CBAVD and 1 CUAVD without observed renal agenesis, 9 CBAVD with renal agenesis allele and the R297W mutation on a homozygous Q1352H background may then reduce CFTR function to a disease-causing level. Login to comment

[hide] CFTR gene mutations in Japanese individuals with c... J Cyst Fibros. 2003 Mar;2(1):14-8. Anzai C, Morokawa N, Okada H, Kamidono S, Eto Y, Yoshimura K
CFTR gene mutations in Japanese individuals with congenital bilateral absence of the vas deferens.
J Cyst Fibros. 2003 Mar;2(1):14-8., [PMID:15463840]

Abstract [show]
Congenital bilateral absence of the vas deferens (CBAVD) is a monosymptomatic disease confined to the male reproductive system with similarity to the phenotype of cystic fibrosis (CF), and mutations in the CFTR gene are highly prevalent in Caucasian CBAVD patients. While CF is very rare in Japan, CBAVD is not. Our previous study demonstrated high prevalence of the 5T allele in the CFTR gene in Japanese CBAVD patients. We analyzed whole exons of the CFTR gene in 19 CBAVD patients and 53 normal individuals using polymerase chain reaction amplification-single strand conformation polymorphism analysis and direct sequencing. Three missense mutations (W216X, G1349S, Q1352H) were found in seven CFTR alleles, and the 5T allele was positive in 11 of 38 CFTR patient alleles. Consequently, 47% of CFTR chromosomes in the patients were affected, and 11 individuals (58%) had at least one mutated CFTR allele. In contrast, three of 53 normal individuals (5.7%) had a missense mutation in one of the CFTR genes, but no 5T allele was detected (both P<0.0001). Mutations of the CFTR gene are closely associated with Japanese patients with CBAVD.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
5 Three missense mutations (W216X, G1349S, Q1352H) were found in seven CFTR alleles, and the 5T allele was positive in 11 of 38 CFTR patient alleles. Login to comment
50 Results Using PCR-SSCP analysis followed by direct sequencing, we could detect three missense mutations in a total of seven CFTR alleles: W216X (779GࡊA) in exon 6a; G1349S (4177GࡊA); and Q1352H (4188GࡊC) in exon 22 (Table 1). Login to comment
51 Q1352H mutation was the most frequent one detected in as many as five individuals with the disease. Login to comment
54 In contrast, in 53 normal individuals similarly tested, E217G was found in one chromosome and Q1352H was in two, but no other mutations were detected (data not shown). Login to comment
61 In particular, five patients were compound heterozygotes: patient 1 was associated with G1349S and Q1352H, patient 2 with W216X and Q1352H, and patients 3, 4 and 5 with Q1352H and 5T. Login to comment
82 Another mutation, Q1352H, which was previously described by other Japanese investigators w7x, is likely the most prevalent alteration in Japan. Login to comment
85 Furthermore, it should be determined in the future whether or not this common Q1352H CF allele might be associated with other types of 'CFTRpathies` including the classical form of CF in the Japanese population w16x. Login to comment
89 This may be true, since three normal individuals had one mutated CFTR allele, two of which were Q1352H, as stated above. Login to comment

[hide] Cystic fibrosis transmembrane conductance regulato... J Cyst Fibros. 2006 Aug;5(3):159-64. Epub 2006 Mar 6. Ngiam NS, Chong SS, Shek LP, Goh DL, Ong KC, Chng SY, Yeo GH, Goh DY
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asians with chronic pulmonary disease: a pilot study.
J Cyst Fibros. 2006 Aug;5(3):159-64. Epub 2006 Mar 6., [PMID:16678503]

Abstract [show]
BACKGROUND: Little is known about the relationship between cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asian patients and severe asthma or idiopathic bronchiectasis. We investigated this potential relationship in the Singaporean Chinese. METHODS: Twenty patients with chronic pulmonary disease, 14 with severe asthma and 6 with idiopathic bronchiectasis, were screened for CFTR mutations by direct gene sequencing. The frequencies of identified putative mutations were compared against 40 unaffected controls and 96 unselected population samples. RESULTS: Three missense mutations (I125T, I556V, and Q1352H) and 1 splice site variant (intron 8 12TG5T) were identified in a total of 10 patients, representing a combined mutant/variant allele frequency of 0.25. These alleles were also observed in the controls, but at a significantly lower allele frequency of 0.09 (P<0.01). Furthermore, the I125T mutation was significantly associated with the idiopathic bronchiectasis sub-group (P<0.05). CONCLUSIONS: The significantly higher frequency of CFTR mutations among patients with chronic pulmonary disease compared with unaffected controls suggests that these mutations may increase risk for disease. The association of I125T with idiopathic bronchiectasis alone suggests that different mutations predispose to different disease.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
4 Results: Three missense mutations (I125T, I556V, and Q1352H) and 1 splice site variant (intron 8 12TG5T) were identified in a total of 10 patients, representing a combined mutant/variant allele frequency of 0.25. Login to comment
34 Asian patients with congenital bilateral absence of vas deferens (CBAVD) have been investigated and in Japanese patients with CBAVD, missense mutations including Q1352H were detected [18]. Login to comment
78 Three missense mutations (I125T in exon 4, I556V in exon 11, and Q1352H in exon 22) and one splice site variant (intron 8 12TG5T) were identified among the patients. Login to comment
88 The incidence of the Q1352H mutation was observed to be higher in the severe asthma patients, where 2 of 14 patients (14.3%) were heterozygous for Q1352H, compared to 1 of 40 normal controls (2.5%) and an estimated population heterozygote frequency of 4.2% (4 in 95) (Table 1). Login to comment
93 Table 1 Frequency of CFTR gene variants in the Singaporean Chinese Variation Genotype Unselected population samples (n =93-96) Healthy controls (n =40) Severe asthma (n =14) Idiopathic bronchiectasis (n =6) I125T I125T/WT 2 1 0 2 WT/WT 94 39 14 4 I556V I556V/WT 12 4 3 0 WT/WT 84 36 11 6 Q1352H Q1352H/WT 4 1 2 0 WT/WT 91 39 12 6 12TG5T 12TG5T/Other 9 1 2 1 Other/Other 84 39 12 5 Table 2 CFTR gene variant allele frequency comparisons between patient and population and normal control groups Variation Allele Unselected population (n =186-192) Healthy controls (n =80) Severe asthma (n =28) P-value Idiopathic bronchiectasis (n =12) P-value I125T Variant 2 1 0 1.000a 2 0.018a,* Wild-type 190 79 28 1.000b 10 0.044b,* I556V Variant 12 4 3 0.415a 0 1.000a Wild-type 180 76 25 0.372b 12 1.000b Q1352H Variant 4 1 2 0.172a 0 1.000a Wild-type 186 79 26 0.163b 12 1.000b 12TG5T 12TG5T 9 1 2 0.640a 1 0.473a Other 177 79 26 0.164b 11 0.245b a P value for disease vs. unselected population. Login to comment
113 Although the higher proportion of the Q1352H mutation in our patient population was not statistically significant, it is likely that this mutation has a role to play in disease causation. Login to comment
114 In a study in a Korean population, it was found that the heterozygote frequency of Q1352H was significantly higher in patients with bronchiectasis and chronic pancreatitis. Login to comment
115 Q1352H was found on molecular studies to be a significant mutation. It is located in the sequence called the ''linker peptide`` of the CFTR. Login to comment
117 The change of the last glutamine into histidine (Q1352H) resulted in defects in protein expression and affected gating properties of single channel kinetics [22]. Login to comment
119 [18] Q1352H was also recently detected in a Korean patient with alcoholic chronic pancreatitis although it was not thought to predispose to the disease [23]. Login to comment
139 The mutations were the I556V and the Q1352H mutations. Login to comment

[hide] PGD for cystic fibrosis patients and couples at ri... Reprod Biomed Online. 2013 May;26(5):420-30. doi: 10.1016/j.rbmo.2013.01.006. Epub 2013 Jan 29. Rechitsky S, Verlinsky O, Kuliev A
PGD for cystic fibrosis patients and couples at risk of an additional genetic disorder combined with 24-chromosome aneuploidy testing.
Reprod Biomed Online. 2013 May;26(5):420-30. doi: 10.1016/j.rbmo.2013.01.006. Epub 2013 Jan 29., [PMID:23523379]

Abstract [show]
Preimplantation genetic diagnosis (PGD) for inherited disorders is presently applied for more than 300 different conditions. The most frequent PGD indication is cystic fibrosis (CF), the largest series of which is reviewed here, totalling 404 PGD cycles. This involved testing for 52 different CFTR mutations with almost half of the cases (195/404 cycles) performed for DeltaF508 mutation, one-quarter (103/404 cycles) for six other frequent mutations and only a few for the remaining 45 CFTR mutations. There were 44 PGD cycles performed for 25 CF-affected homozygous or double-heterozygous CF patients (18 male and seven female partners), which involved testing simultaneously for three mutations, resulting in birth of 13 healthy CF-free children and no misdiagnosis. PGD was also performed for six couples at a combined risk of producing offspring with CF and another genetic disorder. Concomitant testing for CFTR and other mutations resulted in birth of six healthy children, free of both CF and another genetic disorder in all but one cycle. A total of 96 PGD cycles for CF were performed with simultaneous aneuploidy testing, including microarray-based 24-chromosome analysis, as a comprehensive PGD for two or more conditions in the same biopsy material.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
42 [1075C>A; 1079C>A] p.[Gln359Lys; Thr360Lys] Exon 8 1 1 1 4 1 1 R297Q c.890G>A p.Arg297Gln Exon 8 1 1 1 2 0 0 R347P c.1040G>C p.Arg347Pro Exon 8 3 5 2 4 1 1 T338I c.1013C>T p.Thr338Ile Exon 8 1 1 1 2 1 1 DF508 c.1521_1523delCTT p.Phe508del Exon 11 130 195 172 345 88 (4) 92 DI507 c.1519_1521delATC p.Ile507del Exon 11 1 5 5 11 2 1 Q493R c.1478A>G p.Gln493Arg Exon 11 5 5 2 2 2 2 1717-1G-A c.1585-1G>A - Intron 11 6 10 9 18 6 8 G542X c.1624G>T p.Gly542X Exon 12 14 17 15 34 10 10 G551S c.1651G>A p.Gly551Ser Exon 12 1 1 1 2 1 1 G551D c.1652G>A p.Gly551Asp Exon 12 12 22 19 33 7 8 I556V c.1666A>G p.Ile556Val Exon 12 1 2 2 4 1 1 R553X c.1657C>T p.Arg553X Exon 12 3 4 2 4 0 0 R560T c.1679G>C p.Arg560Thr Exon 12 1 1 1 2 1 2 1898+1G-A c.1766 &#b1; 1G>A - Intron 13 1 1 1 2 1 1 2184delA c.2052delA p.Lys684AsnfsX38 Exon 14 1 1 0 0 0 0 G622D c.1865G>A p.Gly622Asp Exon 14 1 1 1 3 0 0 N703S c.2108A>G p.Asn703Ser Exon 14 1 2 2 3 2 2 S737F c.2210C>T p.Ser737Phe Exon 14 1 1 0 0 0 0 2622+1G-A c.2490 &#b1; 1G>A - Intron 14 1 5 5 13 1 1 2752-26A-G c.2620-26A>G - Intron 15 1 2 2 4 0 0 2789+5G-A c.2657 &#b1; 5G>A - Intron 16 3 5 4 8 0 0 3120G-A c.2988G>A - Exon 18 2 2 1 2 1 0 3067-72del c.3067_3072del p.Ile1023_Val1024del Exon 19 1 1 1 1 0 0 I1027T c.3080T>C p.Ile1027Thr Exon 19 1 1 1 1 0 0 L997F c.2991G>C p.Leu997Phe Exon 19 1 2 2 4 1 (1) 0 M1028R c.3083T>G p.Met1028Arg Exon 19 1 1 1 2 1 2 F1052V c.3154T>G p.Phe1052Val Exon 20 1 1 0 0 0 0 Y1092X c.3276C>A p.Tyr1092X Exon 20 1 2 1 2 1 1 A1136T c.3406G>A p.Ala1136Thr Exon 21 1 2 1 2 1 0 D1152H c.3454G>C p.Asp1152His Exon 21 3 7 7 15 1 1 3659 del C c.3528delC p.Lys1177SerfsX15 Exon 22 2 4 3 7 3 3 R1162X c.3484C>T p.Arg1162X Exon 22 1 3 2 5 2 2 S1235R c.3705T>G p.Ser1235Arg Exon 22 2 3 3 5 2 1 3849+10kbC>T c.3717 &#b1; 12191C>T - Intron 22 2 4 4 5 0 0 W1282X c.3846G>A p.Trp1282X Exon 23 15 20 20 42 11 11 N1303K c.3909C>G p.Asn1303Lys Exon 24 9 12 11 24 4 5 Q1352H c.4056G>C p.Gln1352His Exon 25 1 1 1 1 1 1 Total 265 404 345 685 172 (6a ) 175 Values are n unless otherwise stated. Login to comment

[hide] ATP and AMP mutually influence their interaction w... J Biol Chem. 2013 Sep 20;288(38):27692-701. doi: 10.1074/jbc.M113.479675. Epub 2013 Aug 6. Randak CO, Dong Q, Ver Heul AR, Elcock AH, Welsh MJ
ATP and AMP mutually influence their interaction with the ATP-binding cassette (ABC) adenylate kinase cystic fibrosis transmembrane conductance regulator (CFTR) at separate binding sites.
J Biol Chem. 2013 Sep 20;288(38):27692-701. doi: 10.1074/jbc.M113.479675. Epub 2013 Aug 6., [PMID:23921386]

Abstract [show]
Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel in the ATP-binding cassette (ABC) transporter protein family. In the presence of ATP and physiologically relevant concentrations of AMP, CFTR exhibits adenylate kinase activity (ATP + AMP &lrarr2; 2 ADP). Previous studies suggested that the interaction of nucleotide triphosphate with CFTR at ATP-binding site 2 is required for this activity. Two other ABC proteins, Rad50 and a structural maintenance of chromosome protein, also have adenylate kinase activity. All three ABC adenylate kinases bind and hydrolyze ATP in the absence of other nucleotides. However, little is known about how an ABC adenylate kinase interacts with ATP and AMP when both are present. Based on data from non-ABC adenylate kinases, we hypothesized that ATP and AMP mutually influence their interaction with CFTR at separate binding sites. We further hypothesized that only one of the two CFTR ATP-binding sites is involved in the adenylate kinase reaction. We found that 8-azidoadenosine 5'-triphosphate (8-N3-ATP) and 8-azidoadenosine 5'-monophosphate (8-N3-AMP) photolabeled separate sites in CFTR. Labeling of the AMP-binding site with 8-N3-AMP required the presence of ATP. Conversely, AMP enhanced photolabeling with 8-N3-ATP at ATP-binding site 2. The adenylate kinase active center probe P(1),P(5)-di(adenosine-5') pentaphosphate interacted simultaneously with an AMP-binding site and ATP-binding site 2. These results show that ATP and AMP interact with separate binding sites but mutually influence their interaction with the ABC adenylate kinase CFTR. They further indicate that the active center of the adenylate kinase comprises ATP-binding site 2.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
322 Mutations G576A, G550R, and Q1352H have been described in patients with congenital bilateral absence of the vas deferens, a condition that affects men with cystic fibrosis but can also occur in the absence Nucleotide Interactions with the ABC Adenylate Kinase CFTR SEPTEMBER 20, 2013ߦVOLUME 288ߦNUMBER 38 JOURNAL OF BIOLOGICAL CHEMISTRY 27699 of other disease manifestations. Login to comment

[hide] Targeted next-generation sequencing effectively an... Dig Dis Sci. 2015 May;60(5):1297-307. doi: 10.1007/s10620-014-3476-9. Epub 2014 Dec 10. Nakano E, Masamune A, Niihori T, Kume K, Hamada S, Aoki Y, Matsubara Y, Shimosegawa T
Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis.
Dig Dis Sci. 2015 May;60(5):1297-307. doi: 10.1007/s10620-014-3476-9. Epub 2014 Dec 10., [PMID:25492507]

Abstract [show]
BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) gene, responsible for the development of cystic fibrosis, is known as a pancreatitis susceptibility gene. Direct DNA sequencing of PCR-amplified CFTR gene segments is a first-line method to detect unknown mutations, but it is a tedious and labor-intensive endeavor given the large size of the gene (27 exons, 1,480 amino acids). Next-generation sequencing (NGS) is becoming standardized, reducing the cost of DNA sequencing, and enabling the generation of millions of reads per run. We here report a comprehensive analysis of CFTR variants in Japanese patients with chronic pancreatitis using NGS coupling with target capture. METHODS: Exon sequences of the CFTR gene from 193 patients with chronic pancreatitis (121 idiopathic, 46 alcoholic, 17 hereditary, and nine familial) were captured by HaloPlex target enrichment technology, followed by NGS. RESULTS: The sequencing data covered 91.6 % of the coding regions of the CFTR gene by >/= 20 reads with a mean read depth of 449. We could identify 12 non-synonymous variants including three novel ones [c.A1231G (p.K411E), c.1753G>T (p.E585X) and c.2869delC (p.L957fs)] and seven synonymous variants including three novel ones in the exonic regions. The frequencies of the c.4056G>C (p.Q1352H) and the c.3468G>T (p.L1156F) variants were higher in patients with chronic pancreatitis than those in controls. CONCLUSIONS: Target sequence capture combined with NGS is an effective method for the analysis of pancreatitis susceptibility genes.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
7 The frequencies of the c.4056G[C (p.Q1352H) and the c.3468G[T (p.L1156F) variants were higher in patients with chronic pancreatitis than those in controls. Login to comment
88 The patient also had the c.4056G[C (p.Q1352H) variant in a Fig. 1 Graph of the mean depth, median depth, and sequencing coverage for all the 27 exons in the CFTR gene. Login to comment
90 On average, 90.3 % of the coding region was successfully covered by C20 reads Table 2 Non-synonymous CFTR variants detected in this study Exon Non-synonymous variant Amino acid change dbSNP135 Genotype SIFT (score) PolyPhen-2 (score) Alcoholic CP (%) Idiopathic CP (%) Hereditary/ familial CP (%) 2 c.91C[T p.R31C rs1800073 CT D (0.012) PD (0.989) 0/46 (0) 3/121 (2.5) 0/26 (0) 2 c.92G[A p.R31H rs149353983 GA T (0.183) B (0.003) 0/46 (0) 1/121 (0.8) 0/26 (0) 4 c.374T[C p.I125T rs141723617 TC D (0.005) B (0.17) 0/46 (0) 2/121 (1.6) 1/26 (3.8) 10 c.1231A[G p.K411E - AG D (0.015) B (0.233) 0/46 (0) 1/121 (0.8) 0/26 (0) 11 c.1408G[A p.V470M rs213950 GA T (1) B (0) 21/46 (45.7) 65/121 (53.7) 11/26 (42.3) AA 5/46 (10.9) 19/121 (15.7) 1/26 (3.8) 12 c.1666A[G p.I556V rs75789129 AG T (0.536) B (0.334) 2/46 (4.3) 8/121 (6.6) 0/26 (0) GG 0/46 (0) 0/121 (0) 0/26 (0) 13 c.1753G[T p.E585X - GT - - 1/46 (2.2) 0/121 (0) 0/26 (0) 17 c.2869delC p.L957fs - - - 0/46 (0) 1/121 (0.8) 0/26 (0) 21 c.3468G[T p.L1156F rs139729994 GT T (0.163) PD (0.994) 2/46 (4.3) 10/121 (8.3) 2/26 (7.7) TT 1/46 (2.2) 0/121 (0) 0/26 (0) 25 c.4045G[A p.G1349S rs201686600 GA D (0) PD (1) 1/46 (2.2) 0/121 (0) 0/26 (0) 25 c.4056G[C p.Q1352H rs113857788 GC D (0) PD (1) 5/46 (10.9) 11/121 (9.1) 4/26 (15.4) CC 0/46 (0) 0/121 (0) 0/26 (0) 27 c.4357C[T p.R1453W rs4148725 CT D (0) PD (0.999) 3/46 (6.5) 6/121 (5.0) 1/26 (3.8) B benign, CP chronic pancreatitis, D damaging, PD probably damaging, T tolerated, SIFT Sorting Intolerant From Tolerant heterozygous form (Table 6). Login to comment
97 The frequency of the c.4056G[C (p.Q1352H) variant was higher in all patients with CP than that in controls (P = 0.009; Table 3). Login to comment
100 There were no significant difference for any other non-synonymous or synonymous variants detected in the exons Table 3 Comparison of the non-synonymous variant frequencies between the patients with CP and controls Amino acid change Genotype All CP (%) HGVD (%) P value (vs. HGVD) All CP Alcoholic CP Nonalcoholic CP Idiopathic CP Hereditary/ familial CP p.R31C CT 3/193 (1.6) 12/1102 (1.1) 0.48 [0.99 0.41 0.18 [0.99 p.R31H GA 1/193 (0.5) 0 - - - - - p.I125T TC 3/193 (1.6) 5/1102 (0.5) 0.11 [0.99 0.057 0.15 0.13 p.K411E AG 1/193 (0.5) 0 - - - - - p.V470M GA 97/193 (50.3) 573/1199 (47.8) 0.66 0.57 0.68 0.38 0.12 AA 25/193 (13.0) 185/1199 (15.4) p.I556V AG 10/193 (5.2) 78/1150 (6.8) 0.70 0.79 0.81 [0.99 0.45 GG 0/193 (0) 3/1150 (0.3) p.E585X GT 1/193 (0.5) 0 - - - - - p.L957fs 1/193 (0.5) 0 - - - - - p.L1156F GT 14/193 (7.3) 45/1136 (4.0) 0.04 0.06 0.07 0.11 0.30 TT 1/193 (0.5) 1/1136 (0.1) p.G1349S GA 1/193 (0.5) 4/1094 (0.4) 0.56 0.19 [0.99 [0.99 [0.99 p.Q1352H GC 20/193 (10.4) 57/1153 (4.9) 0.009 0.12 0.037 0.17 0.062 CC 0/193 (0) 1/1153 (0.1) p.R1453W CT 10/193 (5.2) 42/1144 (3.7) 0.32 0.25 0.49 0.45 [0.99 CP chronic pancreatitis, HGVB Human Genetic Variation Database P values were determined versus HGVD by the Fisher`s exact test Table 4 Synonymous variants in the exons of the CFTR gene detected in this study Exon Synonymous variant Amino acid change dbSNP135 Genotype Alcoholic CP (%) Idiopathic CP (%) Hereditary/ familial CP (%) 4 c.372C[T p.G124= - CT 0/46 (0) 1/121 (0.8) 0/26 (0) 13 c.1731C[T p.Y577= rs55928397 CT 0/46 (0) 1/121 (0.8) 0/26 (0) 15 c.2562T[G p.T854= rs1042077 TG 20/46 (43.5) 69/121 (57.0) 12/26 (46.2) GG 6/46 (13.0) 18/121 (14.9) 0/26 (0) 23 c.3723C[A p.G1241= rs185065886 CA 1/46 (2.2) 0/121 (0) 0/26 (0) 25 c.3975A[G p.R1325= - AG 0/46 (0) 1/121 (0.8) 0/26 (0) 27 c.4254G[A p.E1418= - GA 0/46 (0) 1/121 (0.8) 0/26 (0) 27 c.4389G[A p.Q1463= rs1800136 GA 1/46 (2.2) 3/121 (2.5) 0/26 (0) CP chronic pancreatitis between all patients with CP and controls (Tables 3, 5). Login to comment
114 Comprehensive analysis by targeted NGS enabled us to identify novel and Table 5 Comparison of the synonymous variant frequencies between the patients with CP and controls Synonymous variant Genotype All CP (%) HGVD (%) P value (vs. HGVD) All CP Alcoholic CP Nonalcoholic CP Idiopathic CP Hereditary/ familial CP c.C372T CT 1/193 (0.5) 0 - - - - - c.1731C[T CT 1/193 (0.5) 0 - - - - - c.2562T[G TG 101/193 (52.3) 528/1154 (45.8) 0.22 0.81 0.11 0.045 0.033 GG 24/193 (12.4) 181/1154 (15.7) c.3723C[A CA 1/193 (0.5) 3/671 (4.5) [0.99 0.23 [0.99 [0.99 [0.99 c.3975A[G AG 1/193 (0.5) 0 - - - - - c.4254G[A GA 1/193 (0.5) 0 - - - - - c.4389G[A GA 4/193 (2.1) 40/1112 (3.6) 0.48 [0.99 0.53 0.81 [0.99 AA 0/193 (0) 1/1112 (0.1) CP chronic pancreatitis, HGVD Human Genetic Variation Database P values were determined against HGVD by the Fisher`s exact test Table 6 Total CFTR sequencing results of patients carrying rare non-synonymous CFTR variants a Pancreatitis-associated mutations in the PRSS1, SPINK1, CTRC, and CPA1 genes Case# Etiology Age at onset Rare variant Additional non-synonymous variants c.1210-34TG(9_13) c.1210-12T(5_9) Mutation in other pancreatitis susceptibility genesa A1 Idiopathic 34 p.R31C/- p.R1453W/- TG11/TG11, 7T/7T - A2 Idiopathic 8 p.R31C/- - TG11/TG12, 7T/7T - A3 Idiopathic 16 p.R31C/- - TG11/TG12, 7T/7T - A4 Idiopathic 10 p.R31H/- - TG11/TG12, 7T/7T - A5 Idiopathic 16 p.I125T/- p.L1156F/- TG11/TG12, 7T/7T CTRC p.R29Q/- A6 Idiopathic 2 p.I125T/- - TG11/TG12, 7T/7T - A7 Hereditary 28 p.I125T/- p.R1453W/- TG11/TG12, 7T/7T - A8 Idiopathic 19 p.K411E/- p/L1156F/- TG11/TG12, 7T/7T - A9 Alcoholic 28 p.E585X/- p.I556V/- TG11/TG11, 7T/7T - A10 Idiopathic 21 p.L957fs/- p.Q1352H/- TG11/TG12, 7T/7T - A11 Alcoholic 40 p.G1349S/- - TG11/TG11, 7T/7T - rare variants in the CFTR gene. Login to comment
134 We found a significant association between the p.Q1352H variant and CP. Login to comment
138 Glutamine at 1,352 is located in the second nucleotide-binding fold of CFTR, and its change to histidine (p.Q1352H) causes reductions in both the protein expression and channel activity of CFTR [40]. Login to comment
142 Indeed, seven out of 25 patients carrying the SPINK1 variant(s) had the CFTR p.Q1352H and/or p.L1156F variants. Login to comment
151 Sequence capture eliminates the necessity of setting up hundreds of PCR, instead allowing for parallel Table 8 Total CFTR sequencing results of patients with SPINK1, PRSS1, CTRC, or CPA1 mutations Case# Etiology CFTR variantsa c.1210-34TG(9_13) c.1210-12T(5_9) SPINK1 PRSS1 CTRC CPA1 B1 Familial p.Q1352H/- TG11/TG12, 7T/7T p.N34S/p.N34S B2 Idiopathic - TG12/TG12, 7T/7T p.N34S/p.N34S B3 Idiopathic - TG11/TG12, 7T/7T p.N34S/p.N34S B4 Idiopathic p.L1156F/-, p.Q1352H/- TG11/TG11, 7T/7T p.N34S/- B5 Idiopathic p.Q1352H/- TG11/TG12, 7T/7T p.N34S/- B6 Idiopathic p.Q1352H/- TG11/TG12, 7T/7T p.N34S/- B7 Idiopathic - TG11/TG12, 7T/7T p.N34S/- B8 Idiopathic - TG11/TG12, 7T/7T p.N34S/- B9 Idiopathic - TG11/TG12, 7T/7T p.N34S/- B10 Idiopathic - TG11/TG12, 7T/7T p.N34S/- B11 Idiopathic - TG11/TG12, 7T/7T p.N34S/- B12 Idiopathic - TG11/TG12, 7T/7T p.N34S/- B13 Idiopathic - TG11/TG12, 7T/7T p.N34S/- B14 Alcoholic - TG12/TG13, 5T/7T p.N34S/- B15 Idiopathic - TG11/TG12, 7T/7T p.N34S/IVS3?2T[C B16 Idiopathic p.R1453W/- TG11/TG11, 7T/7T p.N34S/IVS3?2T[C B17 Idiopathic - TG11/TG12, 7T/7T IVS3?2T[C/IVS3?2T[C B18 Idiopathic - TG11/TG12, 7T/7T IVS3?2T[C/IVS3?2T[C B19 Hereditary p.I125T/-, p.L1156F/- TG11/TG12, 5T/7T IVS3?2T[C/- B20 Familial p.L1156F/- TG11/TG12, 7T/7T IVS3?2T[C/- B21 Idiopathic - TG11/TG12, 7T/7T IVS3?2T[C/- B22 Alcoholic p.Q1352H/- TG11/TG12, 7T/7T IVS3?2T[C/- B23 Alcoholic - TG11/TG12, 7T/7T IVS3?2T[C/- B24 Idiopathic - TG11/TG12, 7T/7T p.P45S/- B25 Idiopathic - TG12/TG12, 7T/7T IVS3?2T[C/- p.R122H/- B26 Hereditary TG11/TG12, 7T/7T p.R122H/- B27 Idiopathic p.I556V/- TG11/TG12, 7T/7T p.N29I/- B28 Idiopathic p.I125T/-, p.L1156F/- TG11/TG12, 7T/7T p.R29Q/- B29 Idiopathic - TG11/TG12, 7T/7T p.T368_Y369ins20/- Nine patients had the non-synonymous CFTR variants, which are probably damaging based on the SIFT or the PolyPhen-2 prediction The p.I556V variant appeared to be benign based on the SIFT or the PolyPhen-2 prediction Case B28 is the same as A5 in Table 6 a We excluded the p.V470M variant from the list because of its similar frequencies in patients and controls enrichment of target regions in a single experiment. Login to comment

[hide] Erratum: Heterogeneous spectrum of CFTR gene mutat... Ann Lab Med. 2015 Jan;35(1):185-6. doi: 10.3343/alm.2015.35.1.185.
Erratum: Heterogeneous spectrum of CFTR gene mutations in Korean patients with cystic fibrosis.
Ann Lab Med. 2015 Jan;35(1):185-6. doi: 10.3343/alm.2015.35.1.185., [PMID:25553309]

Abstract [show]
[This corrects the article on p. 219 in vol. 31.].

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
6 Frequency of CFTR mutations in Korean CF patients Case No. Amino acid change Exon Nucleotide number Nucleotide change Type of mutation Method of detection Familial targeted mutation study Ref Father Mother Brother Sister 1 Q98R Exon 4 293 A>G Missense Sequencing ND - - NA This study L728NfsX38 Exon 13 2,052 delA Frameshift Sequencing ND + + NA 2 IVS 4 579+5 G>A Splicing Sequencing ND ND NA NA This study 3 Q98R Exon 4 293 A>G Missense Sequencing + - + - [15] Q220X Exon 6a 658 C>T Nonsense Sequencing - + - - 4 Q98R Exon 4 293 A>G Missense Sequencing + - NA NA [16] Q1352H Exon 24 4,056 G>C Missense Sequencing - + NA NA 5 IVS 12 1,766+2 T>C Splicing Sequencing + - NA NA [18] N1303KfsX6 Exon 21 3,908 dupA Frameshift Sequencing - + NA NA 6 IVS 17a 3,272-26 A>G Splicing Sequencing MLPA ND ND NA NA [17] Exon14a 2,623-2,751+? Login to comment
9 Frequency of CFTR mutations in Korean CF patients Case No. Amino acidchange Exon Nucleotide number* Nucleotide change Type of mutation Method of detection Familial targeted mutation study Ref Father Mother Brother Sister 1 Q98R Exon 4 293 A>G Missense Sequencing ND - - NA This study K684NfsX38 Exon 13 2,052 delA Frameshift Sequencing ND + + NA 2 IVS 4 579+5 G>A Splicing Sequencing ND ND NA NA This study 3 Q98R Exon 4 293 A>G Missense Sequencing + - + - [15] Q220X Exon 6a 658 C>T Nonsense Sequencing - + - - 4 Q98R Exon 4 293 A>G Missense Sequencing + - NA NA [16] Q1352H Exon 24 4,056 G>C Missense Sequencing - + NA NA 5 IVS 12 1,766+2 T>C Splicing Sequencing + - NA NA [18] N1303KfsX6 Exon 21 3,908 dupA Frameshift Sequencing - + NA NA 6 IVS 17a 3,272-26 A>G Splicing Sequencing ND ND NA NA [17] Exon14a 2,623-2,751+? Login to comment

[hide] Functional characteristics of L1156F-CFTR associat... Am J Physiol Gastrointest Liver Physiol. 2015 Aug 15;309(4):G260-9. doi: 10.1152/ajpgi.00015.2014. Epub 2015 Jun 18. Kondo S, Fujiki K, Ko SB, Yamamoto A, Nakakuki M, Ito Y, Shcheynikov N, Kitagawa M, Naruse S, Ishiguro H
Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese.
Am J Physiol Gastrointest Liver Physiol. 2015 Aug 15;309(4):G260-9. doi: 10.1152/ajpgi.00015.2014. Epub 2015 Jun 18., [PMID:26089335]

Abstract [show]
Although cystic fibrosis is rare in Japanese, measurement of sweat Cl(-) has suggested mild dysfunction of cystic fibrosis transmembrane conductance regulator (CFTR) in some patients with chronic pancreatitis. In the present study, we have investigated the association of CFTR variants and chronic pancreatitis in Japanese and the functional characteristics of a Japanese- and pancreatitis-specific CFTR variant, L1156F. Seventy patients with alcoholic chronic pancreatitis, 18 patients with idiopathic chronic pancreatitis, and 180 normal subjects participated. All exons and their boundaries and promoter region of the CFTR gene were sequenced. Human embryonic kidney-293 cells were transfected with three CFTR variants (M470V, L1156F, and M470V+L1156F), and the protein expression was examined. Xenopus laevis oocytes were injected with the CFTR variants, and bicarbonate (HCO3 (-)) transport activity was examined. CFPAC-1 cells were transfected with the CFTR variants and Cl(-)/HCO3 (-) exchange activity was examined. Six variants (E217G, I556V, M470V, L1156F, Q1352H, and R1453W) were identified in the coding region of the CFTR gene. Cystic fibrosis-causing mutations were not found. The allele frequencies of L1156F and Q1352H in alcoholic chronic pancreatitis (5.0 and 7.9%) were significantly (P < 0.01) higher than those in normal subjects (0.6 and 1.9%). L1156F was linked with a worldwide CFTR variant, M470V. Combination of M470V and L1156F significantly reduced CFTR expression to approximately 60%, impaired CFTR-mediated HCO3 (-)/Cl(-) transport activity to 50-60%, and impaired CFTR-coupled Cl(-)/HCO3 (-) exchange activity to 20-30%. The data suggest that the Japanese-specific CFTR variant L1156F causes mild dysfunction of CFTR and increases the risk of alcoholic chronic pancreatitis in Japanese.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
11 Six variants (E217G, I556V, M470V, L1156F, Q1352H, and R1453W) were identified in the coding region of the CFTR gene. Login to comment
13 The allele frequencies of L1156F and Q1352H in alcoholic chronic pancreatitis (5.0 and 7.9%) were significantly (P b0d; 0.01) higher than those in normal subjects (0.6 and 1.9%). Login to comment
38 Our laboratory`s previous study (13) indicated the association of two types of CFTR variants, c.4056Gb0e;C, p.Arg1352His (Q1352H) and c.4357Cb0e;T, p.Arg1453Trp (R1453W), and chronic pancreatitis in Japanese. Login to comment
39 Defects of protein expression and ion transport of Q1352H-CFTR were confirmed by heterologous expression system, while R1453W-CFTR showed mild reduction of open probability (27). Login to comment
57 Six CFTR variants, c.650Ab0e;G, p.Glu217Gly (E217G); c.1666Ab0e;G, p.Ile556Val (I556V); M470V; L1156F; Q1352H; and R1453W, were detected. Login to comment
132 Six variants (E217G, I556V, M470V, L1156F, Q1352H, and R1453W) were identified in coding regions of the CFTR gene (Table 2). Login to comment
133 The allele frequencies of L1156F and Q1352H in alcoholic chronic pancreatitis (5.0 and 7.9%) were significantly (P b0d; 0.01) higher than those in normal subjects (0.6 and 1.9%). Login to comment
138 Genotypes of CFTR (presence of L1156F and Q1352H, M/V470, poly T, and TG repeats), sex, age, etiology of pancreatitis, presence or absence of pancreatic stone, pancreatic exocrine function (secretin test), sweat Clafa; concentration, and mutations in SPINK1 and PRSS1 are shown. Login to comment
141 The allele frequencies of polymorphisms in the coding regions of CFTR gene ACP ICP NS n 140 36 360 E217G (exon 6a) Glu 137 (97.9) 36 (100) 354 (98.3) Gly 3 (2.1) 0 (0) 6 (1.7) M470V (exon 10) Met 60 (42.9) 14 (38.9) 143 (39.7) Val 80 (57.1) 22 (61.1) 217 (60.3) I556V (exon 11) Ile 138 (98.6) 36 (100) 348 (96.7) Val 2 (1.4) 0 (0) 12 (3.3) L1156F (exon 18) Leu 133 (95.0) 35 (97.2) 358 (99.4) Phe 7 (5.0)* 1 (2.8) 2 (0.6) Q1352H (exon 22) Gln 129 (92.1) 35 (97.2) 353 (98.1) His 11 (7.9)* 1 (2.8) 7 (1.9) R1453W (exon 24) Arg 138 (98.6) 32 (88.9) 353 (98.1) Trp 2 (1.4) 4 (11.1)* 7 (1.9) Values are no. Login to comment
148 CFTR Genotypes Sex Age, yr Etiology Pancreatic Stone Secretin Test* Sweat [Clafa; ] SPINK1 Mutation PRSS1 Mutation Volume MBC Amylase 1 L1156F af9; Q1352H af9; V/V470 af9; 7/7T af9;11/11(TG) M 59 Alcoholic af9; - - 2 L1156F af9; V/V470 af9; 7/7T af9;11/11(TG) M 65 Alcoholic af9; 174.5 96.9 21,524 42.0 - - 3 L1156F af9; V/V470 af9; 7/7T af9;11/12(TG) M 49 Alcoholic - - - 4 L1156F af9; Q1352H af9; M/V470 af9; 7/7T af9;11/12(TG) M 57 Alcoholic af9; 88.9 - 5 L1156F af9; M/V470 af9; 7/7T af9;11/12(TG) M 60 Alcoholic af9; 53.0 50.9 1,627 67.0 - - 6 L1156F af9; M/V470 af9; 7/7T af9;11/12(TG) M 56 Alcoholic af9; 149.0 71.3 6,891 98.9 - - 7 L1156F af9; M/V470 af9; 7/7T af9;11/12(TG) M 51 Alcoholic af9; N34S 8 L1156F af9; M/V470 af9; 7/7T af9;11/12(TG) F 73 Idiopathic af9; 58.9 - - Genotypes of CFTR indicate presence of L1156F and Q1352H, M/V470, poly T, and TG repeats. Login to comment
157 Two patients had the Q1352H variant, which is also associated with alcoholic chronic pancreatitis. Login to comment
258 The association of chronic pancreatitis and three Japanese/ Asian types of CFTR variants (L1156F, Q1352H, and R1453W) were demonstrated in our present and previous (13) studies. Login to comment
263 While Q1352H and R1453W are also found in Koreans (27) and thus categorized to Asian-type CFTR variants, L1156F is probably a Japanese-specific CFTR variant and has not been reported from other countries. Login to comment
268 While Q1352H was also found in patients with congenital bilateral absence of the vas deferens (1) and diffuse panbronchiolitis and R1453W in patients with diffuse panbronchiolitis (Cystic Fibrosis Mutation Database), L1156F has not been found in other CFTR-related diseases. Login to comment