ABCMdb

ABCC7 p.Gln1352His

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Publications

PMID: 16006996 [PubMed] Conseil G et al: "Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters."

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

PMID: 12952861 [PubMed] Lee JH et al: "A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases."

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

PMID: 14998948 [PubMed] Danziger KL et al: "Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis."

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

PMID: 15121783 [PubMed] Fujiki K et al: "Genetic evidence for CFTR dysfunction in Japanese: background for chronic pancreatitis."

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

PMID: 15645635 [PubMed] Naruse S et al: "Do CFTR gene polymorphisms determine the susceptibility to alcoholic chronic pancreatitis?"

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

PMID: 15716623 [PubMed] Ahn KM et al: "Cystic fibrosis in Korean children:a case report identified by a quantitative pilocarpine iontophoresis sweat test and genetic analysis."

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

PMID: 16187186 [PubMed] Lee KH et al: "Mutation analysis of SPINK1 and CFTR gene in Korean patients with alcoholic chronic pancreatitis."

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

PMID: 16435054 [PubMed] Zilfalil BA et al: "Detection of F508del mutation in cystic fibrosis transmembrane conductance regulator gene mutation among Malays."

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

PMID: 17003641 [PubMed] Keiles S et al: "Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis."

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

PMID: 17238030 [PubMed] Naruse S et al: "Is genetic analysis helpful for diagnosing chronic pancreatitis in its early stage?"

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

PMID: 17329263 [PubMed] Ratbi I et al: "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."

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

PMID: 17539902 [PubMed] Chang MC et al: "Spectrum of mutations and variants/haplotypes of CFTR and genotype-phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis."

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

PMID: 17700961 [PubMed] Quinton PM et al: "Too much salt, too little soda: cystic fibrosis."

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

PMID: 17719933 [PubMed] Pall H et al: "Primary sclerosing cholangitis in childhood is associated with abnormalities in cystic fibrosis-mediated chloride channel function."

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

PMID: 18304229 [PubMed] Sakamoto H et al: "Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation associated with a congenital bilateral absence of vas deferens."

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

PMID: 19812525 [PubMed] de Cid R et al: "Independent contribution of common CFTR variants to chronic pancreatitis."

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

PMID: 20021716 [PubMed] Gallati S et al: "Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners."

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

PMID: 20052366 [PubMed] Gee HY et al: "The L441P mutation of cystic fibrosis transmembrane conductance regulator and its molecular pathogenic mechanisms in a Korean patient with cystic fibrosis."

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

PMID: 20233062 [PubMed] van de Vosse E et al: "Distribution of CFTR variations in an Indonesian enteric fever cohort."

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

PMID: 20416310 [PubMed] Ooi CY et al: "Genetic testing in pancreatitis."

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

PMID: 20512161 [PubMed] de Becdelievre A et al: "Notable contribution of large CFTR gene rearrangements to the diagnosis of cystic fibrosis in fetuses with bowel anomalies."

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

PMID: 20879059 [PubMed] Kim KW et al: "Association between cystic fibrosis transmembrane conductance regulator gene mutations and susceptibility for childhood asthma in Korea."

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

PMID: 21779199 [PubMed] Jung H et al: "Heterogeneous spectrum of CFTR gene mutations in Korean patients with cystic fibrosis."

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

PMID: 22749696 [PubMed] Chen JM et al: "Genetics and pathogenesis of chronic pancreatitis: the 2012 update."

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

PMID: 22483971 [PubMed] Li H et al: "Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens."

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

PMID: 22327961 [PubMed] Garg PK et al: "Chronic pancreatitis in India and Asia."

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

PMID: 22271776 [PubMed] Vernooij-van Langen AM et al: "Novel strategies in newborn screening for cystic fibrosis: a prospective controlled study."

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

PMID: 15829248 [PubMed] Lee JE et al: "Gene SNPs and mutations in clinical genetic testing: haplotype-based testing and analysis."

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

PMID: 9272157 [PubMed] Dork T et al: "Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens."

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

PMID: 15463840 [PubMed] Anzai C et al: "CFTR gene mutations in Japanese individuals with congenital bilateral absence of the vas deferens."

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

PMID: 16678503 [PubMed] Ngiam NS et al: "Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asians with chronic pulmonary disease: a pilot study."

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

PMID: 23523379 [PubMed] Rechitsky S et al: "PGD for cystic fibrosis patients and couples at risk of an additional genetic disorder combined with 24-chromosome aneuploidy testing."

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

PMID: 23921386 [PubMed] Randak CO et al: "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."

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

PMID: 25492507 [PubMed] Nakano E et al: "Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis."

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

PMID: 25553309 [PubMed] et al: "Erratum: Heterogeneous spectrum of CFTR gene mutations in Korean patients with cystic fibrosis."

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

PMID: 26089335 [PubMed] Kondo S et al: "Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese."

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