ABCB4 p.Met113Leu
| Predicted by SNAP2: | A: N (53%), C: D (63%), D: D (80%), E: D (85%), F: D (66%), G: D (80%), H: D (75%), I: N (72%), K: D (85%), L: N (57%), N: D (75%), P: D (91%), Q: D (80%), R: D (85%), S: D (59%), T: D (75%), V: N (66%), W: D (80%), Y: D (71%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] ABCB4 sequence variations in young adults with cho... Liver Int. 2009 May;29(5):743-7. Epub 2008 Oct 24. Nakken KE, Labori KJ, Rodningen OK, Nakken S, Berge KE, Eiklid K, Raeder MG
ABCB4 sequence variations in young adults with cholesterol gallstone disease.
Liver Int. 2009 May;29(5):743-7. Epub 2008 Oct 24., [PMID:19018976]
Abstract [show]
BACKGROUND AND AIMS: Mutations in the gene encoding the ABCB4 [adenosine triphosphate (ATP)-binding cassette, sub-family B (MDR/TAP), member 4] transporter lower phosphatidylcholine output into bile and contribute to cholesterol gallstone formation by decreasing the solubility of cholesterol in bile. Mutations in ABCB4 have been identified in patients with low phospholipid-associated cholelithiasis. The aim of the present study was to determine the types and frequencies of ABCB4 mutations in cholecystectomized patients aged <40 years. PATIENTS AND METHODS: Hundred and four patients (mean age 30.6 years, range 12-39) were included in the study and the ABCB4 gene was sequenced. The frequency of missense mutations found in the patient material was measured in 95 healthy controls. The potential functional implications of the ABCB4 missense variations were assessed by computerized analysis (BLOSUM62 and Grantham substitution matrices, polymorphism phenotyping and sorting intolerant from tolerant). RESULTS: One patient was heterozygous for a frameshift mutation (c.1399_1400ins10/p.Y467F fsX25). Another patient was heterozygous for a nonsense mutation (c.3136C>T/p.R1046X). These two mutations are considered detrimental to ABCB4 protein function. In addition, six missense mutations were found in the ABCB4 gene, and three of these were only present in patients. CONCLUSION: In our study, <2% of young gallstone patients were found to be heterozygous for detrimental ABCB4 mutations. The functional implication of several missense mutations remains to be clarified. Thus, mutations in the ABCB4 gene are a rare cause of gallstone disease.
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No. Sentence Comment
62 These were c.337A4G/p.M113L, c.523A4G/p.T175A, c.1584G4 C/ p.E528D, c.1769G4 A/p.R590Q, c.1954A4G/p.R652G and c.3318G4 C/p.Q1106H).
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ABCB4 p.Met113Leu 19018976:62:22
status: NEW69 The c.337A4G variant is located in exon 5 (c.337A4G) and results in change of residue 113 from a methionine to leucine (p.M113L).
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ABCB4 p.Met113Leu 19018976:69:122
status: NEW86 Four of the eight identified ABCB4 gene variants have not been reported before (p.M113L, p.Q1106H, p.Y467F fsX25 and p.R1046X).
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ABCB4 p.Met113Leu 19018976:86:82
status: NEW88 Table 1. Summary of patient characteristics having ABCB4 gene variations with possible effects on the ABCB4 protein and the occurrence of these variations in healthy controls Patient (ID) (n = 104) Gender/ethnicity Age Indication for surgery Gallstone Location Nucleotide change Peptide change Status Controls (n = 95) 1-16 Female Exon 16 c.1954A 4 G p.R652G 9 17-22 Female/Norwegian 21 Choledocholithiasis Multiple, 5 mm Exon 6 c.523A 4 G p.T175A heterozygous 3 Female/Iraq 25 Cholecystolithiasis Multiple, 5-10 mm Female/Norwegian 28 Cholecystolithiasis Two, 15 mm Female/African 31 Cholecystitis Multiple, 5 mm1solitary, 20 mm Female/Norwegian 32 Cholecystolithiasis Multiple, 5 mm Female/Norwegian 34 Cholecystolithiasis Multiple, 5-10 mm 23 Female/Norwegian 32 Cholecystolithiasis Two, 20 mm Exon 14 c.1584G 4 C p.E528D heterozygous 0 24-25 Female/Norwegian 23 Cholecystolithiasis Multiple, 5 mm Exon 15 c.1769G 4 A p.R590Q heterozygous 1 Female/Norwegian 37 Cholecystolithiasis Multiple, o 5 mm 26 Female/Norwegian 40 Cholecystitis Solitary, 30 mm Exon 25 c.3136C 4 T p.R1046X heterozygous - 27 Female/Pakistani 30 Cholecystolithiasis Three, 10 mm Exon 13 c.1399_1400 ins10 p.Y467F fsX25 heterozygous - 28 Ã Female/Pakistani 32 Cholecystolithiasis Multiple, o 5 mm Exon 5 c.337A 4 G p.M113L heterozygous 0 Exon 26 c.3318G 4 C p.Q1106H 0 The variation p.R652G, considered to be without functional significance for the ABCB4 product, is shown without patient characteristics (16 patients).
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ABCB4 p.Met113Leu 19018976:88:1296
status: NEW94 Grantham values range from 5 to 215; low values ( o 50) indicate chemical similarity and high values ( 4 50) indicate more radical differences) Scoring Systems for Nonsynonymous Variants Amino acid change Grantham Blosum62 SIFT PolyPhen EC/EU p.M113L 15 2 0.17 1.211 EC p.T175A 58 0 0 0.845 EC p.E528D 45 2 0.25 0.617 EC p.R590Q 43 1 0 1.951 EC p.R652G 125 À 2 0.42 1.237 EU p.Q1106H 24 0 0.03 0.185 EC Blosum62 values range from À 4 to13, with negative values indicating less acceptable and positive values indicating more acceptable substitutions.
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ABCB4 p.Met113Leu 19018976:94:245
status: NEW109 One Pakistani patient was apparently compound heterozygous for p.M113L and p.Q1106H.
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ABCB4 p.Met113Leu 19018976:109:65
status: NEW111 None of the controls were found to be heterozygous for c.337A4G (p.M113L) and c.3318G 4 C (p.Q1106H).
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ABCB4 p.Met113Leu 19018976:111:67
status: NEW112 Because the controls were of Norwegian origin, c.337A4G (p.M113L) and c.3318G 4 C (p.Q1106H), the finding in this patient could just reflect that these two variations are common among individuals of Pakistani origin.
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ABCB4 p.Met113Leu 19018976:112:59
status: NEW113 The predictive tools suggest that neither p.M113L nor p.Q1106H affects the function of ABCB4.
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ABCB4 p.Met113Leu 19018976:113:44
status: NEW114 Thus, at present, we cannot conclude about the roles of p.M113L or p.Q1106H in gallstone disease.
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ABCB4 p.Met113Leu 19018976:114:58
status: NEW