ABCMdb

PMID: 20010382

Ho RH, Leake BF, Kilkenny DM, Meyer Zu Schwabedissen HE, Glaeser H, Kroetz DL, Kim RB
Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability.
Pharmacogenet Genomics. 2010 Jan;20(1):45-57., [PubMed]

Sentences

No. Mutations Sentence Comment

138 ABCB11 p.Arg1153Cys ABCB11 p.Gly982Arg Functional analysis of bile salt export pump variants A panel of expression plasmids comprising wild-type BSEP, nine nonsynonymous BSEP variants, and two known PFIC2 BSEP missense mutants, 2944G > A (Gly982Arg) and 3457C >T (Arg1153Cys), was constructed for functional studies. Login to comment 144 ABCB11 p.Asn591Ser ABCB11 p.Ile206Val ABCB11 p.Gln558His ABCB11 p.Glu1186Lys In addition, several rare BSEP polymorphisms, including 616A > G (Ile206Val), 1674G > C (Gln558His), 1772A > G (Asn591Ser), and 3556G > A (Glu1186Lys) were also associated with significantly impaired taurocholate transport compared with wild-type BSEP, exhibited by retained increased intracellular taurocholate accumulation (P < 0.05). Login to comment 145 ABCB11 p.Glu297Gly Another rare BSEP variant, 890A > G (Glu297Gly), tended to have impaired taurocholate transport function, but did not reach statistical significance (P = 0.051). Login to comment 146 ABCB11 p.Val444Ala ABCB11 p.Met677Val Two common BSEP polymorphisms, 1331T > C (Val444Ala) and 2029A > G (Met677Val), were not associated with significant changes in taurocholate transport activity. Login to comment 156 ABCB11 p.Glu297Gly ABCB11 p.Val444Ala ABCB11 p.Met677Val ABCB11 p.Asn591Ser ABCB11 p.Ile206Val ABCB11 p.Ser56Leu ABCB11 p.Glu592Gln ABCB11 p.Gln558His ABCB11 p.Glu1186Lys Calnexin, an intracellular resident Table 1 Single-nucleotide polymorphisms in ABCB11 Allele frequencies (%) SNP rs number Amino acid change African-American European-American Asian-American Mexican-American Pacific Islanders 108T > C rs3815675 Synonymous 1.5 1.5 25 5.0 21.4 167C > T rs11568361 Ser56Leu 0.5 0 0 0 0 174C > T rs11568362 Synonymous 0.5 0 0 0 0 270T > C rs414877 Synonymous 3.0 3.5 5.0 0 7.1 402C > T rs11568377 Synonymous 3.5 0 0 0 0 585G > C rs11568365 Synonymous 0.5 0 0 0 0 616A > G rs11568357 Ile206Val 2.5 0 0 0 0 696G > T rs11568358 Synonymous 0 0.5 0 0 0 807T > C rs2287616 Synonymous 2.0 0.5 23.3 5.0 21.4 890A > G rs11568372 Glu297Gly 0 0.5 0 0 0 957A > G rs7563233 Synonymous 31.5 0.5 0 15.0 0 1281C > T rs11568360 Synonymous 0.5 0 0 0 0 1331T > C rs2287622 Val444Ala 53.0 57.1 66.7 50.0 92.9 1671C > T rs11568368 Synonymous 0 0.5 0 0 0 1674G > C rs11568369 Gln558His 0 0.5 0 0 0 1772A > G rs11568367 Asn591Ser 0 0.5 0 0 0 1774G > C rs11568370 Glu592Gln 0 0.5 0 0 0 1791G > T rs11568371 Synonymous 0 0.5 0 0 0 2029A > G rs11568364 Met677Val 15.0 5.5 1.7 5.0 0 2412A > G rs11568373 Synonymous 8.0 0 0 5.0 0 3084A > G rs97692 Synonymous 28.6 54.6 63.3 37.5 21.4 3258A > G rs11568359 Synonymous 7.0 0 0 0 0 3435A > G rs11568366 Synonymous 1.0 0 0 0 0 3556G > A rs1521808 Glu1186Lys 2.5 0 0 0 0 Allele frequencies for single-nucleotide polymorphisms (SNPs) in ABCB11 were determined from a DNA panel of ethnically defined healthy individuals - African-Americans (n = 100), European-Americans (n = 100), Asian-Americans (n = 30), Mexican-Americans (n = 10) and Pacific Islanders (n = 7). Login to comment 230 ABCB11 p.Val444Ala Indeed, Lang et al. [24] found that a common BSEP variant, 1331T > C (Val444Ala), was more frequently observed in DC patients than in drug-induced hepatocellular injury patients or healthy controls. Login to comment 231 ABCB11 p.Val444Ala However, when expressed and functionally characterized in Sf9 membrane vesicles, there were no significant differences in protein expression or taurocholate transport activity in the Val444Ala variant versus wild-type BSEP, consistent with our data. Login to comment 232 ABCB11 p.Val444Ala The same group previously reported that the Val444Ala variant was associated with low-protein expression from a bank of 110 liver samples from individuals undergoing liver resection for various hepatic diseases [32], though it was not statistically significant. Login to comment