ABCMdb

ABCB4 p.Arg788Trp

ClinVar:	c.2363G>A , p.Arg788Gln N , Benign
Predicted by SNAP2:	A: D (85%), C: D (80%), D: D (95%), E: D (91%), F: D (95%), G: D (91%), H: D (85%), I: D (91%), K: D (85%), L: D (91%), M: D (91%), N: D (95%), P: D (95%), Q: D (95%), S: D (95%), T: D (91%), V: D (91%), W: D (95%), Y: D (91%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D,

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Publications
[hide] A mutation in the canalicular phospholipid transpo... Hepatology. 2008 Oct;48(4):1157-66. Gotthardt D, Runz H, Keitel V, Fischer C, Flechtenmacher C, Wirtenberger M, Weiss KH, Imparato S, Braun A, Hemminki K, Stremmel W, Ruschendorf F, Stiehl A, Kubitz R, Burwinkel B, Schirmacher P, Knisely AS, Zschocke J, Sauer P
A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults.
Hepatology. 2008 Oct;48(4):1157-66., [PMID:18781607]

Abstract [show]
Cholestatic liver disease (CLD) is a major cause of progressive liver damage and liver failure. Several forms of biliary cirrhosis are caused by mutations in specific genes. We sought to identify a genetic defect in a family with CLD impossible to assign to a distinct pathogenic entity. Clinical and histopathological characterization of the family members, microarray-based single-nucleotide polymorphism genotyping, and analysis of candidate genes were performed. Among six of 11 siblings severely affected by idiopathic CLD in a family from a population isolate in Transylvania, three died of cirrhosis (aged 5, 7, and 43 years) and three had adult-onset disease with small duct cholangiopathy, including ductopenia. Others were mildly affected and experienced intrahepatic cholestasis of pregnancy, miscarriages, or stillbirth. Pedigree studies revealed distant parental consanguinity. Genome-wide linkage analysis and autozygosity mapping yielded a single maximal lod-score of 3.88 on chromosome 7q21.1-7q22, excluding other genomic loci. Sequencing of ABCB4 at this locus revealed a novel missense mutation c.2362C>T (p.Arg788Trp) which cosegregated with severity of disease. Bile from a mutation homozygote showed a reduced phosphatidylcholine/bile acid ratio, consistent with reduced ABCB4 phosphatidylcholine transport activity. CONCLUSION: We show that a missense mutation in ABCB4 is a cause for ductopenic CLD in adulthood. Allelic status correlated with severity of liver disease ranging from intrahepatic cholestasis of pregnancy through fibrosis to cirrhosis and death in childhood and adulthood. Mutational analysis of ABCB4 should be generally considered in all patients with cholestatic liver disease of unknown etiology regardless of age and onset of disease.

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Sentences [show]
No. Sentence Comment
8 Sequencing of ABCB4 at this locus revealed a novel missense mutation c.2362C>T (p.Arg788Trp) which cosegregated with severity of disease. Login to comment
147 Whereas ABCB1 has not been described as associated with known disease, mutations in ABCB4 can cause PFIC3, characterized by cholestasis in early childhood and cirrhotic liver failure before adulthood, and cholesterol cholelithiasis.22 Moreover, mutations in ABCB4 are associated with ICP.23,24 Direct sequencing of ABCB4 in I.1 revealed homozygosity for a single sequence variant, c.2362CϾT (p.R788W, Arg788Trp) in exon 19. c.2362C is the first base of a triplet encoding the polar amino acid arginine. Login to comment
149 Sequencing of other family members revealed that c.2362CϾT (R788W) precisely cosegregated with CLD. Login to comment
192 Sequencing of ABCB4 revealed the missense mutation c.2362CϾT (p.R788W) for which siblings suffering from progressive liver damage were homozygous and family members showing only ICP or subtle histopathological changes were heterozygous. Login to comment