ABCMdb

ABCC7 p.Lys68Glu

ClinVar:	c.204A>T , p.Lys68Asn ? , not provided c.202A>G , p.Lys68Glu ? , not provided
CF databases:	c.202A>G , p.Lys68Glu (CFTR1) ? , This mutation was found in a male Turkish patient (first reported Aug 4, 1997). His sweat chloride was 60 meq/l and showed lung disease at age of 26 months. His other CF mutation was later reported to be 406+3T->C (on March 23, 1998). c.204A>T , p.Lys68Asn (CFTR1) ? , This mutation was detected in a single Turkish CF patient of Syrian origin. The second mutation is yet unknown. The mutation segregates with haplotype C.
Predicted by SNAP2:	A: D (66%), C: D (75%), D: D (91%), E: D (80%), F: D (85%), G: D (85%), H: D (53%), I: D (80%), L: D (66%), M: D (75%), N: D (63%), P: D (85%), Q: D (53%), R: N (66%), S: N (61%), T: D (63%), V: D (80%), W: D (91%), Y: D (85%),
Predicted by PROVEAN:	A: N, C: D, D: N, E: N, F: D, G: N, H: D, I: D, L: D, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: D, W: D, Y: D,

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[hide] A new approach for identifying non-pathogenic muta... Hum Genet. 2000 Feb;106(2):172-8. Bombieri C, Giorgi S, Carles S, de Cid R, Belpinati F, Tandoi C, Pallares-Ruiz N, Lazaro C, Ciminelli BM, Romey MC, Casals T, Pompei F, Gandini G, Claustres M, Estivill X, Pignatti PF, Modiano G
A new approach for identifying non-pathogenic mutations. An analysis of the cystic fibrosis transmembrane regulator gene in normal individuals.
Hum Genet. 2000 Feb;106(2):172-8., [PMID:10746558]

Abstract [show]
Given q as the global frequency of the alleles causing a disease, any allele with a frequency higher than q minus the cumulative frequency of the previously known disease-causing mutations (threshold) cannot be the cause of that disease. This principle was applied to the analysis of cystic fibrosis transmembrane conductance regulator (CFTR) mutations in order to decide whether they are the cause of cystic fibrosis. A total of 191 DNA samples from random individuals from Italy, France, and Spain were investigated by DGGE (denaturing gradient gel electrophoresis) analysis of all the coding and proximal non-coding regions of the gene. The mutations detected by DGGE were identified by sequencing. The sample size was sufficient to select essentially all mutations with a frequency of at least 0.01. A total of 46 mutations was detected, 20 of which were missense mutations. Four new mutations were identified: 1341+28 C/T, 2082 C/T, L1096R, and I11131V. Thirteen mutations (125 G/C, 875+40 A/G, TTGAn, IVS8-6 5T, IVS8-6 9T, 1525-61 A/G, M470V, 2694 T/G, 3061-65 C/A, 4002 A/G, 4521 G/A, IVS8 TG10, IVS8 TG12) were classified as non-CF-causing alleles on the basis of their frequency. The remaining mutations have a cumulative frequency far exceeding q; therefore, most of them cannot be CF-causing mutations. This is the first random survey capable of detecting all the polymorphisms of the coding sequence of a gene.

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79 Out of the 20 missense mutations, three (G85E, ∆F508, and N1303K) are certainly CF-causing, and several (R31C, K68E, R75Q, I148T, V562L, G576A-R668C, L997F, F1052V, S1235R) have been described in congenital bilateral absence of the vas deferens, in disseminated bronchiectasis, in pancreatitis, or in atypical CF cases mutations as reported in the CFGAC website (). Login to comment
96 Moreover, 1525-61 A/G (i 9) and 3601-65 C/A (i 18) were detected by SSCA performed in the Spanish sample only (14/82 and 12/80, respectively); these mutations were not identifiable by DGGE as used in the present work The totals are: a378; b362; c380; d356 genes eCertainly a CF-causing mutations fThe most common allele at this site is (TTGA)7 gThe most common allele at this site is T7 hThe frequency shown is that of the M allele Mutation Position North-Central Southern Spain Total East Italy Italy France 82 genes 100 genes 100 genes 100 genes 382 genes % 125 G/C 5`UTR 1 2 7 3 13 3.4 R31C 2 1 1 1 0 3 0.8 K68E 3 1 0 0 0 1 0.3 R75Q 3 1 1 2 0 4 1.0 G85Ee 3 0 1 0 0 1 0.3 406-6 T/C i 3 0 0 1 0 1 0.3 I148T 4 1 0 0 0 1 0.3 621+3 A/G i 4 0 1 0 0 1 0.3 R170H 5 1 0 0 0 1 0.3 875+40 A/G i 6a 11 5 5 2 23 6.0 (TTGA)6 f i 6a 17 11 7 13 48 12.6 1341+28 C/T i 8 1 0 0 0 1 0.3 IVS8-6g T5 i 8 8 2 4 3/78 17a 4.5 IVS8-6g T9 i 8 10 7 10 11/78 38a 10.0 M470Vh 10 42 30 39 27 138 36.1 I506V 10 1 0 0 0 1 0.3 ∆F508e 10 1 0 2 0 3 0.8 1716 G/A 10 2 1 0 5 8 2.1 V562L 12 0 0 1 0 1 0.3 G576A 12 1 0/80 1 0 2b 0.6 G622D 13 0 0/80 1 0 1b 0.3 R668C 13 1 0/80 1 0 2b 0.6 2082 C/T 13 1 0/80 0 0 1b 0.3 2377 C/T 13 0 0/80 0 1 1b 0.3 2694 T/G i 14a 33 23 33 14/80 103c 27.1 2752-15 C/G i 14b 0 3 0 0 3 0.8 3041-71 G/C i 15 0 1 2 0 3 0.8 L997F 17a 0 2 0 0 2 0.5 I1027T 17a 1 0 0 0 1 0.3 F1052V 17b 1 0 0 0 1 0.3 L1096R 17b 0 0 1 0 1 0.3 3417 A/T 17b 1 0 1 0 2 0.5 I1131V 18 0 1 0 0 1 0.3 R1162L 19 0 1 0 0 1 0.3 3690 A/G 19 0 0 0 1/80 1c 0.3 S1235R 19 1 0 0 0 1 0.3 4002 A/G 20 2 3 3 3/80 11c 2.9 4005+28insA i 20 0 1 0 0 0.3 4029 A/G 21 1 0 0 0 1 0.3 N1303Ke 21 1 0 0 0 1 0.3 4404 C/T 24 1 0 1 0 2 0.5 4521 G/A 24 21 16 14/80 15/76 66d 18.5 Total 165 113 137 98 513 encountered in the present survey are possible. Login to comment

[hide] Highest heterogeneity for cystic fibrosis: 36 muta... Am J Med Genet. 2002 Dec 1;113(3):250-7. Kilinc MO, Ninis VN, Dagli E, Demirkol M, Ozkinay F, Arikan Z, Cogulu O, Huner G, Karakoc F, Tolun A
Highest heterogeneity for cystic fibrosis: 36 mutations account for 75% of all CF chromosomes in Turkish patients.
Am J Med Genet. 2002 Dec 1;113(3):250-7., 2002-12-01 [PMID:12439892]

Abstract [show]
We analyzed the CFTR locus in 83 Turkish cystic fibrosis patients to identify mutations, haplotypes, and the carrier frequency in the population. We detected 36 different mutations in 125 (75%) of the total 166 CF chromosomes. Seven novel mutations were identified: four missense (K68E, Q493P, E608G, and V1147I), two splice-site (406 -3T > C and 3849 +5G > A), and one deletion (CFTRdele17b,18). The data showed that the Turkish population has the highest genetic heterogeneity at the CFTR locus reported so far. The results of this thorough molecular analysis at the CFTR locus of a population not of European descent shows that CF is not uncommon in all such populations. The large number of mutations present, as well as the high heterogeneity in haplotypes associated with the mutations suggests that most of the mutations have persisted for a long time in the population. Consistently, the carrier frequency is assessed to be high, indicating that the disease in the population is ancient.

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2 Seven novel mutations were identified: four missense (K68E, Q493P, E608G, and V1147I), two splice-site (406 À3T > C and 3849 þ 5G > A), and one deletion (CFTRdele17b,18). Login to comment
8 KEY WORDS: CF; Turkish; K68E; Q493P; E608G; V1147I; 406 À 3T > C; 3849 þ 5G > A; CFTRdele17b, 18 INTRODUCTION Cystic fibrosis (CF) is the most common autosomal recessive disorder in populations with European ancestry with about 1:25 carrier frequency with regional variation. Login to comment
58 Novel Mutations We identified seven novel mutations, each observed only in one CF patient of a total 260 individuals with various phenotypes such as CF, bronchiectasis and unconfirmed CF, with the exception of K68E, which we found in some patients with pulmonary disease. Login to comment
61 The substituted residues in the missense mutations have been conserved in human, bovine, Xenopus, dogfish, and mouse, except for mutation K68E. Login to comment
63 K68E An A ! Login to comment
92 Sequencing results for six of the novel CF mutations: (a) 406 À 3T > C (sense); (b) V1147I (sense); (c) K68E (sense); (d) 3849 þ 5G > A (antisense); (e) Q493P (sense); (f) E608G (sense). Login to comment
94 The patient is described above as a compound heterozygote for the novel mutation K68E. Login to comment
133 It is most likely that E92K had been misidentified as E92X and K68E as K68N, because mutations affected the same nucleotides. Login to comment

[hide] Extensive molecular analysis of patients bearing C... J Mol Diagn. 2012 Jan;14(1):81-9. Epub 2011 Oct 20. Amato F, Bellia C, Cardillo G, Castaldo G, Ciaccio M, Elce A, Lembo F, Tomaiuolo R
Extensive molecular analysis of patients bearing CFTR-related disorders.
J Mol Diagn. 2012 Jan;14(1):81-9. Epub 2011 Oct 20., [PMID:22020151]

Abstract [show]
Cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (CFTR-RDs) may present with pancreatic sufficiency, normal sweat test results, and better outcome. The detection rate of mutations is lower in CFTR-RD than in classic CF: mutations may be located in genes encoding proteins that interact with CFTR or support channel activity. We tested the whole CFTR coding regions in 99 CFTR-RD patients, looking for gene mutations in solute carrier (SLC) 26A and in epithelial Na channel (ENaC) in 33 patients who had unidentified mutations. CFTR analysis revealed 28 mutations, some of which are rare. Of these mutations, RT-PCR demonstrated that the novel 1525-1delG impairs exon 10 splicing; by using minigene analysis, we excluded the splicing effect of three other novel intronic variants. Analysis of SLC26A genes revealed several variants, some of which are novel, that did not affect mRNA expression. Other mutations occurred in the ENaC genes encoding the ENaC subunits, but their frequency did not significantly differ between patients and controls. Our data, although obtained on a preliminary cohort of CFTR-RD patients, exclude a role of mutations in SLC26A and in SCNN genes in the pathogenesis of such disease; we confirm that CFTR analysis has a relevant role in CFTR-RD patients; and it appears mandatory to use CFTR scanning techniques and approaches to reveal the effect of novel mutations.

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69 Allele Frequency and CFTR Mutations in Patients Bearing CFTR-RDs Mutation (traditional name) HGVS nomenclature15 CBAVD (118 alleles)* RP (42 alleles)* DB (38 alleles)* Total (198 alleles)* TG12-T5-470V 34 (28.8) 2 (4.8) 10 (26.3) 46 (23.2) F508del c.1521_1523del 19 (16.1) 7 (16.7) 4 (10.5) 30 (15.2) 3195del6 c.3063_3069del 9 (7.6) 0 0 9 (4.5) N1303K c.3909CϾG 3 (2.5) 1 (2.4) 4 (10.5) 8 (4.0) G542X c.1624GϾT 4 (3.4) 1 (2.4) 1 (2.6) 6 (3.0) D1152H c.3454GϾC 1 (0.8) 2 (4.8) 2 (5.3) 5 (2.5) G85E c.254GϾA 2 (1.7) 3 (7.1) 0 5 (2.5) 1525-1delG c.1394de 3 (2.5) 1 (2.4) 0 4 (3.0) 4016insT c.3885insT 2 (1.7) 1 (2.4) 0 3 (1.5) 2789ϩ5GϾA c.2657ϩ5GϾA 0 3 (7.1) 0 3 (1.5) Q1476X c.4426CϾT 3 (2.5) 0 0 3 (1.5) 2183AAϾG c.2051_2052delinsG 1 (0.8) 1 (2.4) 0 2 (1.0) R553X c.1657CϾT 1 (0.8) 1 (2.4) 0 2 (1.0) L568F c.1704GϾT 2 (1.7) 0 0 2 (1.0) R1158X c.3472CϾT 2 (1.7) 0 0 2 (1.0) V920M c.2758GϾA 1 (0.8) 0 1 (2.6) 2 (1.0) 711ϩ1GϾT c.579ϩ1GϾT 0 1 (2.4) 0 1 (0.5) D614G c.1841AϾG 1 (0.8) 0 0 1 (0.5) 2184insA c.2052del 0 1 (2.4) 0 1 (0.5) 621ϩ1GϾT c.489ϩ1GϾT 1 (0.8) 0 0 1 (0.5) R1438W c.4312CϾT 0 1 (2.4) 0 1 (0.5) E193X c.577GϾT 0 1 (2.4) 0 1 (0.5) G1244E c.3731GϾA 1 (0.8) 0 0 1 (0.5) K68E c.202AϾG 1 (0.8) 0 0 1 (0.5) R347P c.1040GϾC 1 (0.8) 0 0 1 (0.5) 621ϩ3AϾG c.489ϩ3AϾG 1 (0.8) 0 0 1 (0.5) L997F c.2991GϾC 0 1 (2.4) 0 1 (0.5) F508C c.1523TϾG 1 (0.8) 0 0 1 (0.5) Total 94 (79.7) 28 (66.7) 22 (57.9) 144 (72.7) Undetected 24 (20.3) 14 (33.3) 16 (42.1) 54 (27.3) *Data are given as number (percentage). Login to comment
96 The 504CϾG (G124G) variant was found in a single chromosome from a CBAVD patient in cis with the K68E mutation; 621ϩ16ϾT, identified in a CBAVD patient bearing the F508del/Q1476X genotype; the novel variant was in cis Table 2. Login to comment
144 This detection rate is higher than that reported for other patients affected by CBAVD,20 RP,21-24 or DB.25-28 Most previous studies tested restricted mutation panels for first-level analysis, whereas we used sequencing analysis, and 11 mutations identified in our study (3195del6, Q1476X, L568F, V920M, 1525-1delG, D614G, R1438W, E193X, K68E, 621ϩ3AϾG, and L997F), present in approximately 13% of chromosomes of CFTR-RD patients, are not included in most mutation panels. Login to comment

[hide] Analysis of the CFTR gene in Iranian cystic fibros... J Cyst Fibros. 2008 Mar;7(2):102-9. Epub 2007 Jul 27. Alibakhshi R, Kianishirazi R, Cassiman JJ, Zamani M, Cuppens H
Analysis of the CFTR gene in Iranian cystic fibrosis patients: identification of eight novel mutations.
J Cyst Fibros. 2008 Mar;7(2):102-9. Epub 2007 Jul 27., [PMID:17662673]

Abstract [show]
BACKGROUND: Cystic fibrosis (CF) is the most common inherited disorder in Caucasian populations, with over 1400 mutations identified in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Mutations in the CFTR gene may be also causative for CBAVD (Congenital Bilateral Absence of the Vas Deferens). The type and distribution of mutations varies widely between different countries and/or ethnic groups, and is relatively unknown in Iran. We therefore performed a comprehensive analysis of the CFTR gene in Iranian CF patients. METHODS: 69 Iranian CF patients, and 1 CBAVD patient, were analysed for mutations in the complete coding region, and its exon/intron junctions, of their CFTR genes, using different methods, such as ARMS (amplification refractory mutation system)-PCR, SSCP (single stranded conformation polymorphism) analysis, restriction enzyme digestion analysis, direct sequencing, and MLPA (Multiplex Ligation-mediated Probe Amplification). RESULTS: CFTR mutation analysis revealed the identification of 37 mutations in 69 Iranian CF patients. Overall, 81.9% (113/138) CFTR genes derived from Iranian CF patients could be characterized for a disease-causing mutation. The CBAVD patient was found to be homozygous for the p.W1145R mutation. The most common mutations were p.F508del (DeltaF508) (18.1%), c.2183_2184delAAinsG (2183AA>G) (6.5%), p.S466X (5.8%), p.N1303K (4.3%), c.2789+5G>A (4.3%), p.G542X (3.6%), c.3120+1G>A (3.6%), p.R334W (2.9%) and c.3130delA (2.9%). These 9 types of mutant CFTR genes totaled for 52% of all CFTR genes derived from the 69 Iranian CF patients. Eight mutations, c.406-8T>C, p.A566D, c.2576delA, c.2752-1_2756delGGTGGCinsTTG, p.T1036I, p.W1145R, c.3850-24G>A, c.1342-?_1524+?del, were found for the first time in this study. CONCLUSIONS: We identified 37 CFTR mutations in 69 well characterized Iranian CF patients, obtaining a CFTR mutation detection rate of 81.9%, the highest detection rate obtained in the Iranian population so far. These findings will assist in genetic counseling, prenatal diagnosis and future screening of CF in Iran.

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36 of chromosomes p.K68E E3 A to G at 334 Lys to Glu at 68 1 c.406-8TNC I3 T to C at 406-8 mRNA splicing defect? Login to comment
155 Possible explanations for failure to detect all mutations are: the mutations that are in intron sequences far from coding Table 3 CFTR mutation panel recommended for screening in Iranian CF patients Mutation Number of chromosomes Frequency p.F508del 25 18.1% c.2183_2184delAAinsG 9 6.5% p.S466X 8 5.8% p.N1303K 6 4.3% c.2789+5GNA 6 4.3% p.G542X 5 3.6% c.3120+1GNA 5 3.6% p.R334W 4 2.9% c.3130delA 4 2.9% Total 72 52.0% Table 4 Clinical features and some polymorphisms in 7 Iranian patients; in these patients a mutation could only be found on one CFTR gene Genotype PI/PS Sweat (Cl- ) TGm Tn (In8) GATT (In6a) 1001+11 (In6b) M470V p.K68E/U⁎ PI 80 TG10-T7_TG10-T7 GATT 7/7 C A c.406-8TNC/U PI 50 TG12-T7_TG11-T7 GATT 6/7 C A/G c.406-3TNC/U PI 90 TG11-T7_TG11-T7 GATT 7/7 C G p.R170H/U PS 80 TG11-T7_TG10-T7 GATT 7/7 C A/G c.3850-24GNA/U PI 55 TG11-T7_TG11-T7 GATT 7/7 C G c.2789+5GNA/U PI 50 TG11-T7_TG10-T7 GATT 7/7 C A/G c.2043delG/U PS 70 TG12-T7_TG10-T7 GATT 6/7 C A ⁎Unknown mutations; PS, indicates pancreatic sufficient; PI, pancreatic sufficient. Login to comment
154 Possible explanations for failure to detect all mutations are: the mutations that are in intron sequences far from coding Table 3 CFTR mutation panel recommended for screening in Iranian CF patients Mutation Number of chromosomes Frequency p.F508del 25 18.1% c.2183_2184delAAinsG 9 6.5% p.S466X 8 5.8% p.N1303K 6 4.3% c.2789+5GNA 6 4.3% p.G542X 5 3.6% c.3120+1GNA 5 3.6% p.R334W 4 2.9% c.3130delA 4 2.9% Total 72 52.0% Table 4 Clinical features and some polymorphisms in 7 Iranian patients; in these patients a mutation could only be found on one CFTR gene Genotype PI/PS Sweat (Cl- ) TGm Tn (In8) GATT (In6a) 1001+11 (In6b) M470V p.K68E/UÌe; PI 80 TG10-T7_TG10-T7 GATT 7/7 C A c.406-8TNC/U PI 50 TG12-T7_TG11-T7 GATT 6/7 C A/G c.406-3TNC/U PI 90 TG11-T7_TG11-T7 GATT 7/7 C G p.R170H/U PS 80 TG11-T7_TG10-T7 GATT 7/7 C A/G c.3850-24GNA/U PI 55 TG11-T7_TG11-T7 GATT 7/7 C G c.2789+5GNA/U PI 50 TG11-T7_TG10-T7 GATT 7/7 C A/G c.2043delG/U PS 70 TG12-T7_TG10-T7 GATT 6/7 C A Ìe;Unknown mutations; PS, indicates pancreatic sufficient; PI, pancreatic sufficient. Login to comment

[hide] Interference with ubiquitination in CFTR modifies ... Mol Cell Biol. 2014 Jul;34(14):2554-65. Lee S, Henderson MJ, Schiffhauer E, Despanie J, Henry K, Kang PW, Walker D, McClure ML, Wilson L, Sorscher EJ, Zeitlin PL
Interference with ubiquitination in CFTR modifies stability of core glycosylated and cell surface pools.
Mol Cell Biol. 2014 Jul;34(14):2554-65., [PMID:24777605]

Abstract [show]
It is recognized that both wild-type and mutant CFTR proteins undergo ubiquitination at multiple lysines in the proteins and in one or more subcellular locations. We hypothesized that ubiquitin is added to specific sites in wild-type CFTR to stabilize it and at other sites to signal for proteolysis. Mass spectrometric analysis of wild-type CFTR identified ubiquitinated lysines 68, 710, 716, 1041, and 1080. We demonstrate that the ubiquitinated K710, K716, and K1041 residues stabilize wild-type CFTR, protecting it from proteolysis. The polyubiquitin linkage is predominantly K63. N-tail mutants, K14R and K68R, lead to increased mature band CCFTR, which can be augmented by proteasomal (but not lysosomal) inhibition, allowing trafficking to the surface. The amount of CFTR in the K1041R mutant was drastically reduced and consisted of bands A/B, suggesting that the site in transmembrane 10 (TM10) was critical to further processing beyond the proteasome. The K1218R mutant increases total and cell surface CFTR, which is further accumulated by proteasomal and lysosomal inhibition. Thus, ubiquitination at residue 1218 may destabilize wild-type CFTR in both the endoplasmic reticulum (ER) and recycling pools. Small molecules targeting the region of residue 1218 to block ubiquitination or to preserving structure at residues 710 to 716 might be protein sparing for some forms of cystic fibrosis.

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300 Table 3 lists the findings: K14X (stop), K68E, K68N, K710X (stop), K1080Q, K1080R, and K1080I mutations already exist in human genes. Login to comment