ABCMdb

PMID: 20422497

Pauli-Magnus C, Meier PJ, Stieger B
Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy.
Semin Liver Dis. 2010 May;30(2):147-59. Epub 2010 Apr 26., [PubMed]

Sentences

No. Mutations Sentence Comment

8 ABCB11 p.Val444Ala Besides rare mutations that have been linked to drug-induced cholestasis, the common p.V444A polymorphism of BSEP has been identified as a potential risk factor. Login to comment 77 ABCB11 p.Val444Ala Although high GGT values were present in the majority of ICP patients with an ABCB4 mutation, genetic ABCB11 dysfunction was postulated in low GGT cases.98,103 Two Swiss studies conducted in independent ICP collectives first suggested the BSEP p.V444A polymorphism as the ICP susceptibility factor, with the homozygous and heterozygous state for the alanine in position 444 being significantly more frequent in ICP women than in healthy pregnant controls.66,104 Very interestingly, the ABCB11 genotype in position 444 also correlated with serum bile acid levels, with carriers of the alanine showing higher serum bile acid levels than carriers of the valine allele. Login to comment 79 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly ABCB11 p.Val444Ala ABCB11 p.Asn591Ser ABCB11 p.Asn591Ser In the same study, heterozygosity for the BSEP mutations p.E297G, p.D482G, and p.N591S formerly associated with benign and progressive forms of familial intrahepatic cholestasis type 2 were found in four, one, and two ICP patients, respectively, allowing the extrapolation that 1% of European ICP cases are caused by these mutations.105 Although the molecular and mechanistic basis for p.V444A and p.N591S were not apparent, in silico structural and functional analysis suggests that p.E297G and p.D482G destabilizes the protein fold of BSEP, leading to decreased taurocholate transport in case of p.E297G.105,106 In addition, decreased hepatic BSEP expression,107,108 and very recently, significantly reduced hepatic mRNA levels109 was reported in healthy human liver tissue carrying the alanine allele in position 444 of BSEP, which could predispose to the development of ICP by way of decreased canalicular availability of BSEP. Login to comment 81 ABCC4 p.Met173Thr Of these variants, p.M173T, which is located in the nucleotide-binding domain of the second zinc finger significantly associated with ICP and was shown to have a markedly reduced capacity to activate the ABCB11 promoter in vitro.110 Although the effect of this variant on MDR3 expression has not been studied, it is likely that activation of the ABCB4 promoter is also reduced. Login to comment 82 ABCB4 p.Ser320Phe In line with this, a recent report of an ICP patient suffering from alterations in three genes: p.S320F in ABCB4 (previously described in a patient with ICP113 ), p.A444V in ABCB11, and c.-1G> T in FXR,114 again highlights the role of FXR as a factor associated with ICP. Login to comment 84 ABCB11 p.Gly855Arg Specifically, a heterozygous p.G855R mutation in BSEP leading to highly impaired taurocholate transport was associated with noninflammatory cholestasis and highly elevated serum bile acid levels in a young patient under the first use of an oral ethinylestradiol/gestodene combination for contraception.115 Interestingly, the mother and the maternal grandmother of the patient, who carried the same mutation had a history of ICP. Login to comment 125 ABCB11 p.Asp676Tyr ABCB4 p.Ile764Leu Specifically, full-length sequencing of ABCB11 and ABCB4 revealed a heterozygous p.D676Y mutation in BSEP observed in a patient taking fluvas- tatin and a heterozygous p.I764L mutation in MDR3 observed in a patient taking risperidone:115 both suffered from hepatocellular cholestasis. Login to comment 127 ABCB4 p.Ile764Leu In the case of BSEP, in vitro taurocholate transport was unchanged for the mutated protein whereas the impact of the p.I764L mutation on MDR3 expression and function was not investigated. Login to comment 128 ABCB11 p.Val444Ala In the same study, the BSEP p.V444A polymorphism was observed significantly more frequent in patients with drug-induced cholestasis than in patients with drug-induced hepatocellular injury and healthy controls, with the AA phenotype being encountered in 61% of cholestatic patients compared with 31% and 32% in patients with hepatocellular injury and healthy controls, respectively. Login to comment