ABCMdb

PMID: 25027376

Kubitz R, Droge C, Kluge S, Stindt J, Haussinger D
Genetic variations of bile salt transporters.
Drug Discov Today Technol. 2014 Jun;12:e55-67. doi: 10.1016/j.ddtec.2014.03.006., [PubMed]

Sentences

No. Mutations Sentence Comment

89 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly ABCB11 p.Asn591Ser Among these p.E297G, p.D482G and p.N591S belong to the more frequent mutations. Login to comment 90 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly While homozygosity of p.E297G or p.D482G is linked to PFIC-2, heterozygosity of these mutations was detected in about 1.4% of 491 patients with intrahepatic cholestasis of pregnancy (ICP) [17]. Login to comment 95 ABCB11 p.Val444Ala ABCB11 p.Val444Ala Patients with ICP or CIC have a higher prevalence of the BSEP polymorphism p.V444A/c.1331T>C (exchange of valine to alanine at amino acid position 444; 'p` stands for 'protein`, 'c` stands for 'coding DNA`) [17,72]. Login to comment 100 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly ABCB11 p.Asn591Ser ABCB11 p.Arg1050Cys ABCB11 p.Ala570Thr For example, the two 'BRIC-2 mutations` p.A570T and p.R1050C had lower expression levels than the 'ICP mutation` p.N591S, but higher expression levels as compared to the PFIC-2 mutations p.D482G and p.E297G [59]. Login to comment 101 ABCB11 p.Gly374Ser However, the mutation p.G374S is an exception of this relationship. Login to comment 110 ABCB11 p.Asp482Gly For example reduced splicing and exon skipping was reported for the typical PFIC-2 mutation c.1445A>G (p.D482G), but also for the frequent synonymous variant c.3084A>G (p.A1028A) of BSEP [7] (Table 1). Login to comment 112 ABCB11 p.Glu297Gly ABCB11 p.Arg1268Gln ABCB11 p.Gly238Val ABCB11 p.Arg1153Cys ABCB11 p.Gly982Arg The missense mutations p.G238V, p.E297G, p.G982R, p.R1153C and p.R1268Q all led to a reduced expression at the apical membrane, when expressed in MDCK cells [124]. Login to comment 113 ABCB11 p.Gly982Arg ABCB11 p.Tyr818Phe It was shown in vitro that the two BSEP mutations p.Y818F and p.G982R caused intracellular retention of BSEP. Login to comment 114 ABCB11 p.Val444Ala ABCB11 p.Val444Ala When in addition to these two mutations the common BSEP polymorphism p.V444A was present, complete degradation of triple-mutated BSEP via ERAD was observed [46], suggesting that p.V444A contributes to impaired stability of BSEP. Login to comment 115 ABCB11 p.Val444Ala ABCB4 p.Ser320Phe A Vol. 12, 2014 Drug Discovery Today: Technologies | Transporter assays patient homozygous for p.V444A of BSEP and p.S320F of MDR3 (ABCB4), suffered from a severe form of ICP. Login to comment 116 ABCB11 p.Val444Ala BSEP expression (but not MDR3 expression) was massively reduced during cholestasis [49] underscoring the potential role of p.V444A for half-life of BSEP. Furthermore, transporter recycling at the canalicular membrane may influence the expression level. Login to comment 117 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly For the two common BSEP mutations p.E297G and p.D482G it has been reported that treatment with 4-phenylbutyrate prolongs half-life at the canalicular membrane and consecutively overall expression of BSEP [29]. Login to comment 129 ABCB11 p.Val444Ala The frequent BSEP polymorphism p.V444A represents the mildest form of BSEP deficiency. Login to comment 130 ABCB11 p.Val444Ala An association between p.V444A and drug-induced liver injury [61] has been demonstrated. Login to comment 132 ABCB11 p.Val444Ala The association of p.V444A with such disturbances may be explained by the decreased expression of BSEP in the presence of the polymorphism [71], leading to increased bile salt concentrations in hepatocytes. Login to comment 133 ABCB11 p.Val444Ala Furthermore, hepatitis C infected patients, who are homozygous for valine of p.V444A have less severe liver fibrosis [37] and some but not all HCV-cohorts show better treatment responses towards interferon/ribavirin treatment [54]. Login to comment 137 ABCB11 p.Val444Ala ABCB11 p.Gly982Arg ABCB11 p.Arg1231Gln ABCB11 p.Glu186Gly ABCB11 p.Ile206Val ABCB11 p.Arg432Thr ABCB11 p.Arg1231Trp ABCB11 p.Arg1050Cys ABCB11 p.Arg1128His ABCB11 p.Ala926Pro ABCB11 p.Gln558His ABCB11 p.Ala570Thr ABCB11 p.Ala570Thr ABCB11 p.Glu1186Lys ABCB11 p.Glu1186Lys ABCB11 p.Glu297Lys ABCB11 p.Thr463Ile ABCB11 p.Glu135Lys ABCB11 p.Thr586Ile ABCB11 p.Arg1128Cys ABCB11 p.Ser1154Pro ABCB11 p.Arg1153His ABCB11 p.Ser1144Arg ABCB11 p.Gly1116Arg ABCB11 p.Tyr818Phe ABCB11 p.Ala1110Glu ABCB11 p.Arg832Cys ABCB11 p.Gly374Ser BSEP/Bsep NTCP ASBT Exon skipping E186G G1116R G319G R1128C T463I R1128H A926P E1186K A1028Aa R1231W A1110E Aberrant splicing E297K R1153H R832C S1154P S1144R No splice product T586I R1231Q Reduced plasma membrane expression E135K A570T I223T E297Gb N591Sb V444A R1050C Intracellular retention Y818F G982R Reduced or absent bile salt transport A570T R432T A64T K314E V98Ic M264V I206V Q558H I223T C144Y P290S E297Gb N591Sb S267F L243P G374S E1186K I279T T262M a A1028A induces significant exon skipping in vitro but probably not in vivo (unpublished data; Dro &#a8;ge, Ha &#a8;ussinger, Kubitz). Login to comment 138 ABCB11 p.Glu297Gly ABCB11 p.Asn591Ser b Some variants (such as E297G or N591S of BSEP) may affect transport handling on different levels. Login to comment