Characterization of mutations in ATP8B1 associated with hereditary cholestasis

Leo W. J. Klomp, Julie C. Vargas, Saskia W. C. van Mil, Ludmila Pawlikowska, Sandra S. Strautnieks, Michiel J. T. van Eijk, Jenneke A. Juijn, Carlos Pabón‐Peña, Lauren B. Smith, Joseph A. DeYoung, Jane A. Byrne, Justijn Gombert, Gerda van der Brugge, Ruud Berger, Irena Jankowska, Joanna Pawlowska, Erica Villa, A. S. Knisely, Richard J. Thompson, Nelson B. Freimer, Roderick H. J. Houwen, Laura N. Bull

Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC) are clinically distinct hereditary disorders. PFIC patients suffer from chronic cholestasis and develop liver fibrosis. BRIC patients experience intermittent attacks of cholestasis that resolve spontaneously. Mutations in ATP8B1 (previously FIC1) may result in PFIC or BRIC. We report the genomic organization of ATP8B1 and mutation analyses of 180 families with PFIC or BRIC that identified 54 distinct disease mutations, including 10 mutations predicted to disrupt splicing, 6 nonsense mutations, 11 small insertion or deletion mutations predicted to induce frameshifts, 1 large genomic deletion, 2 small inframe deletions, and 24 missense mutations. Most mutations are rare, occurring in 1-3 families, or are limited to specific populations. Many patients are compound heterozygous for 2 mutations. Mutation type or location correlates overall with clinical severity: missense mutations are more common in BRIC (58% vs. 38% in PFIC), while nonsense, frameshifting, and large deletion mutations are more common in PFIC (41% vs. 16% in BRIC). Some mutations, however, lead to a wide range of phenotypes, from PFIC to BRIC or even no clinical disease. ATP8B1 mutations were detected in 30% and 41%, respectively, of the PFIC and BRIC patients screened.