Characterization of mutations inATP8B1associated with... : Hepatology (original) (raw)

Original Articles

Characterization of mutations in ATP8B1 associated with hereditary cholestasis

Klomp, Leo W. J.*,1,2,†; Vargas, Julie C.3; van Mil, Saskia W. C.2; Pawlikowska, Ludmila3, 4, 5; Strautnieks, Sandra S.6; van Eijk, Michiel J. T.2; Juijn, Jenneke A.1; Pabón-Peña, Carlos5; Smith, Lauren B.5; DeYoung, Joseph A.5; Byrne, Jane A.6; Gombert, Justijn1; van der Brugge, Gerda1; Berger, Ruud1; Jankowska, Irena7; Pawlowska, Joanna7; Villa, Erica8; Knisely, A. S.6; Thompson, Richard J.6; Freimer, Nelson B.5, 9; Houwen, Roderick H. J.2; Bull, Laura N.*,3,‡

1Department of Metabolic and Endocrine Diseases, University Medical Center, Utrecht, The Netherlands

2Department of Pediatric Gastroenterology, University Medical Center, Utrecht, The Netherlands

3UCSF Liver Center Laboratory and Department of Medicine, San Francisco General Hospital, San Francisco, CA

4Program in Biomedical Sciences, Department of Psychiatry and Liver Center, University of California, San Francisco, San Francisco, CA

5Neurogenetics Laboratory, Department of Psychiatry and Liver Center, University of California, San Francisco, San Francisco, CA

6Institute of Liver Studies, King’s College Hospital, Denmark Hill, London, United Kingdom

7Department of Gastroenterology,Hepatology, and Immunology, The Children’s Memorial Health Institute, Warsaw, Poland

8Department of Internal Medicine/Gastroenterology, University of Modena; e reggio Emilia Medical School, Modena, Italy

9Department of Psychiatry and Human Genetics, University of California, Los Angeles, Los Angeles, CA

E-mail:[email protected]; [email protected]

*Address reprint requests to: Leo W. J. Klomp, Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, Wilhelmina Children’s Hospital, Room KC.02.069.1, Lundlaan 6, 3584 EA Utrecht, The Netherlands; Laura N. Bull, University of California, San Francisco Liver Center Laboratory, San Francisco General Hospital, 1001 Potrero Avenue, Building 40, Room 4102, San Francisco, CA 94110

†fax: 31-30-2504295

‡fax: 415-641-0517

Received September 23, 2003; Accepted March 24, 2004; previously published online June 30, 2004

Abstract

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. Supplementary material for this article can be found on the Hepatology website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html) and at www.atp8b1-primers.nl (Hepatology 2004;40:27-38.)