ABCMdb

PMID: 19018976

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., [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCB4 p.Tyr467Phe Results: One patient was heterozygous for a frameshift mutation (c.1399_1400ins10/p.Y467F fsX25). Login to comment 8 ABCB4 p.Arg1046* Another patient was heterozygous for a nonsense mutation (c.3136C 4 T/p.R1046X). Login to comment 58 ABCB4 p.Arg1046* This leads to a premature stop codon, p.R1046X. Login to comment 59 ABCB4 p.Tyr467Phe Another patient was heterozygous for a 10 base pair insertion in exon (13) (c.1399_1400 ins10), resulting in a frameshift, followed by a premature stop codon (p.Y467F fsX25). Login to comment 62 ABCB4 p.Arg590Gln ABCB4 p.Thr175Ala ABCB4 p.Glu528Asp ABCB4 p.Arg652Gly ABCB4 p.Met113Leu 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). Login to comment 65 ABCB4 p.Glu528Asp This mutation replaces residue 528 glutamate to an aspartate (p.E528D). Login to comment 68 ABCB4 p.Glu528Asp This may indicate that p.E528D may increase the risk for gallstone disease. Login to comment 69 ABCB4 p.Met113Leu 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). Login to comment 78 ABCB4 p.Thr175Ala ABCB4 p.Thr175Ala Six patients and three controls were heterozygous for c.523A4G in exon 6, which changed residue 175 from threonine to alanine (p.T175A). Login to comment 79 ABCB4 p.Arg590Gln The variant c.1769G4 A in exon 19 results in the amino acid change p.R590Q (argini- ne4 glutamine). Login to comment 80 ABCB4 p.Arg652Gly ABCB4 p.Arg652Gly The nucleotide change c.1954A4G replaces residue 652 arginine to glycine (p.R652G) and was found in 16 patients, and one patient was homozygous. Login to comment 86 ABCB4 p.Tyr467Phe ABCB4 p.Arg1046* ABCB4 p.Met113Leu Four of the eight identified ABCB4 gene variants have not been reported before (p.M113L, p.Q1106H, p.Y467F fsX25 and p.R1046X). Login to comment 88 ABCB4 p.Arg590Gln ABCB4 p.Thr175Ala ABCB4 p.Glu528Asp ABCB4 p.Arg652Gly ABCB4 p.Arg652Gly ABCB4 p.Tyr467Phe ABCB4 p.Arg1046* ABCB4 p.Met113Leu 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). Login to comment 94 ABCB4 p.Arg590Gln ABCB4 p.Thr175Ala ABCB4 p.Glu528Asp ABCB4 p.Arg652Gly ABCB4 p.Met113Leu 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. Login to comment 99 ABCB4 p.Tyr467Phe ABCB4 p.Arg1046* The nonsense mutation c.3136C 4 T resulting in a premature stop codon p.R1046X and the insertion c.1399_1400 ins10 resulting in frameshift, followed by a premature stop codon (p.Y467F fsX25), are the two mutations that most probably affected the function of the ABCB4 protein in our patient material. Login to comment 105 ABCB4 p.Glu528Asp We consider the nonsynonymous variation, c.1584G 4 C (p.E528D), a potentially pathogenic mutation. Login to comment 107 ABCB4 p.Glu528Asp This suggests that p.E528D may increase the risk for gallstone disease. Login to comment 108 ABCB4 p.Glu528Asp However, the prediction tools PolyPhen, Grantham and BLOSUM62 indicated that p.E528D would most probably not affect the function of the ABCB4 protein (Table 3). Login to comment 109 ABCB4 p.Met113Leu One Pakistani patient was apparently compound heterozygous for p.M113L and p.Q1106H. Login to comment 111 ABCB4 p.Met113Leu None of the controls were found to be heterozygous for c.337A4G (p.M113L) and c.3318G 4 C (p.Q1106H). Login to comment 112 ABCB4 p.Met113Leu 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. Login to comment 113 ABCB4 p.Met113Leu The predictive tools suggest that neither p.M113L nor p.Q1106H affects the function of ABCB4. Login to comment 114 ABCB4 p.Met113Leu Thus, at present, we cannot conclude about the roles of p.M113L or p.Q1106H in gallstone disease. Login to comment 115 ABCB4 p.Thr175Ala Six patients were found to have the variation c.523A 4G (p.T175A), resulting in an allele frequency of 6/208 (2.9%). Login to comment 117 ABCB4 p.Thr175Ala p.T175A has already been detected in a larger cohort of Caucasian volunteers (17, 18). Login to comment 119 ABCB4 p.Arg652Gly The c.1954A 4G (p.R652G) variation was found in one patient, which was homozygous for the variation in addition to 15 patients with heterozygous variations. Login to comment 136 ABCB4 p.Tyr467Phe ABCB4 p.Arg1046* The mutations found were c.3136C 4 T/p.R1046X and c.1399_1400ins10/p.Y467F fsX25. Login to comment