A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults†‡

Abstract

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, microarraybased 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. (HEPATOLOGY 2008;48:1157-1166

Two ABCB4 point mutations of strategic NBD-motifs do not prevent protein targeting to the plasma membrane but promote MDR3 dysfunction

“…The p.(L481R) mutation was identified in three out of seven affected siblings belonging to family A, whereas the already characterized p.(Y403H) mutation 6,14 was identified in four affected members belonging to other two families. According to what is generally described, [13][14][15] the genotypes reported here show that (i) two mutant ABCB4 alleles are associated with severe early-onset of intrahepatic cholestasis characterized by a rapid course toward terminal liver failure. In particular, the infant bearing the homozygous p.(Y403H) mutation was diagnosed as PFIC-3 at the age of 3 months, and at the age of 3 years presented compensated cirrhosis with portal hypertension; (ii) a single mutant allele can be associated with hepatobiliary diseases with less significant and highly variable clinical features.…”

“…10 In the following years, a growing number of ABCB4 mutations have been identified also in adult subjects affected by juvenile cholelithiasis, 11 drug-induced cholestasis 12 and idiopathic cholestasis of the adulthood. 13 Recently, our group highlighted that the simple heterozygous ABCB4 genotype could be a discrete risk factor for a wide range of hepatobiliary diseases, including the PFIC-3 phenotype with variable disease expressivity, 14 primary biliary cirrhosis and primary sclerosing cholangitis (Crosignani A, personal communication). To date, 146 disease-associated ABCB4 mutations are reported in the Human Genome Mutation Database (http://www.hgmd.org/; release date 14 December 2012); of them, 87 (about 60%) are predicted to substitute a single amino acid and 30 of these (about 34%) fall within the N-terminal NBD.…”

“…However, even if several ABCB4 defects have been linked to diverse hepatobiliary diseases, the detrimental effect of most missense mutations on protein function remains mainly speculative, as predicted by in silico analysis only. Because of the invasiveness of biliary sampling, in vivo evaluation of the content of biliary PC has been performed occasionally 13,15 and hence both the evidences of human diseases linked to ABCB4 mutations and the related pathogenic mechanisms associated with floppase dysfunction require further understanding.…”

Analysis of mutations of MDR3 exons 9 and 23 in infants with parenteral nutrition-associated cholestasis

“…The reduced expression of MDR3 reduces lecithin secretion and elevates vesicle cholesterol. It can also lead to bile duct damage, gallstone deposition, inflammation and biliary liver lesions (30)(31)(32).…”

Primary Sclerosing Cholangitis: Diagnostic and Therapeutic Problems

“…It has been suggested that confirmatory ERC after MRC should only be considered for cases in which the clinical findings are inconsistent with the diagnosis of PSC, such as cases involving underlying cirrhosis, cases in which the clinical suspicion is moderately high and cases with negative MRC results [8]. Therefore, in patients with unclear cholestasis, an ERC might be indicated to firmly exclude PSC and/or to obtain specimens for further analysis [4,9]. The detection of dominant strictures is of major importance because endoscopic treatment of these strictures is aimed to relieve biliary obstruction and to improve prognosis.…”