ABCMdb

PMID: 19260995

Hsu YC, Chen HL, Wu MZ, Liu YJ, Lee PH, Sheu JC, Chen CH
Adult progressive intrahepatic cholestasis associated with genetic variations in ATP8B1 and ABCB11.
Hepatol Res. 2009 Jun;39(6):625-31. Epub 2009 Feb 24., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCB11 p.Val444Ala Serial liver histopathology demonstrated cirrhosis resulting from progressive persistent cholestatic injury. Genetic sequencing studies for the entire coding exons of ATP8B1 and ABCB11 uncovered a heterozygous missense mutation 1798 C->T (R600W) in ATP8B1, and a homozygous nucleotide substitution 1331 T->C (V444A) in ABCB11. Login to comment 8 ABCB11 p.Val444Ala Genetic sequencing analysis revealed a heterozygous ATP8B1 mutation (R600W) and a homozygous ABCB11 polymorphism (V444A). Login to comment 64 ABCB11 p.Val444Ala A heterozygous missense mutation c.1798C>T (p.R600W) was found in ATP8B1 and a homozygous nucleotide substitution c.1331T>C (p.V444A) was found in ABCB11. Login to comment 65 ABCB11 p.Val444Ala The R600W had been found to be associated with BRIC8 and the V444A had been reported to be a polymorphism associated with intrahepatic cholestasis of pregnancy,15,16 BRIC12 and drug-induced cholestasis.17 DISCUSSION THE UNIQUE FEATURE of this case was the adult onset progressive intrahepatic cholestasis with low g-GT. Login to comment 86 ABCB11 p.Val444Ala ABCB11 p.Val444Ala ABCB11 p.Val444Ala ABCB11 p.Val444Ala ABCB11 p.Val444Ala ABCB11 p.Glu186Gly ABCB4 p.Ser320Phe In contrast, homozygous V444A of ABCB11 was originally considered as a frequent polymorphism in the western population, which might be associated with intrahepatic cholestasis of pregnancy.15 Keitel et al. investigated an unusual case of severe intrahepatic cholestasis of pregnancy and demonstrated that a homozygous V444A in combination with a homozygous MDR3 mutation (S320F) was associated with diminished canalicular BSEP.16 Kubitz et al. reported compound heterozygosity of V444A and E186G in a BRIC-2 patient with decreased canalicular BSEP.12 Lang et al. described a significant association of V444A with drug-related cholestasis and concluded that V444A was susceptible for cholestasis under certain challenges, based on their in vitro study of BSEP expression and its transporter activity.17 It is possible that the multi-genetic alterations in this patient contributed to an inherited susceptibility for secondary insults, which caused the phenotype with disease onset at a later age than usual genetic diseases. Login to comment