Clinical phenotype and molecular analysis of a homozygous ABCB11 mutation responsible for progressive infantile cholestasis

The bile salt export pump (BSEP) plays an important role in biliary secretion. Mutations in ABCB11, the gene encoding BSEP, induce progressive familial intrahepatic cholestasis type 2 (PFIC2), which presents with severe jaundice and liver dysfunction. A less severe phenotype, called benign recurrent intrahepatic cholestasis type 2, is also known. About 200 missense mutations in ABCB11 have been reported. However, the phenotype-genotype correlation has not been clarified. Furthermore, the frequencies of ABCB11 mutations differ between Asian and European populations. We report a patient with PFIC2 carrying a homozygous ABCB11 mutation c.386G>A (p.C129Y) that is most frequently reported in Japan. The pathogenicity of BSEP^C129Y has not been investigated. In this study, we performed the molecular analysis of this ABCB11 mutation using cells expressing BSEP^C129Y. We found that trafficking of BSEP^C129Y to the plasma membrane was impaired and that the expression of BSEP^C129Y on the cell surface was significantly lower than that in the control. The amount of bile acids transported via BSEP^C129Y was also significantly lower than that via BSEP^WT. The transport activity of BSEP^C129Y may be conserved because the amount of membrane BSEP^C129Y corresponded to the uptake of taurocholate into membrane vesicles. In conclusion, we demonstrated that c.386G>A (p.C129Y) in ABCB11 was a causative mutation correlating with the phenotype of patients with PFIC2, impairment of biliary excretion from hepatocytes, and the absence of canalicular BSEP expression in liver histological assessments. Mutational analysis in ABCB11 could facilitate the elucidation of the molecular mechanisms underlying the development of intrahepatic cholestasis.