title: Characterization of mutations in ATP8B1 associated with hereditary cholestasis.
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.
authors.affiliation: Department of Metabolic and Endocrine Diseases, University Medical Center, Utrecht, The Netherlands. l.klomp@wkz.azu.nl
authors.forename: Leo W J
authors.initials: LW
authors.lastname: Klomp
authors.forename: Julie C
authors.initials: JC
authors.lastname: Vargas
authors.forename: Saskia W C
authors.initials: SW
authors.lastname: van Mil
authors.forename: Ludmila
authors.initials: L
authors.lastname: Pawlikowska
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Strautnieks
authors.forename: Michiel J T
authors.initials: MJ
authors.lastname: van Eijk
authors.forename: Jenneke A
authors.initials: JA
authors.lastname: Juijn
authors.forename: Carlos
authors.initials: C
authors.lastname: Pabón-Peña
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Smith
authors.forename: Joseph A
authors.initials: JA
authors.lastname: DeYoung
authors.forename: Jane A
authors.initials: JA
authors.lastname: Byrne
authors.forename: Justijn
authors.initials: J
authors.lastname: Gombert
authors.forename: Gerda
authors.initials: G
authors.lastname: van der Brugge
authors.forename: Ruud
authors.initials: R
authors.lastname: Berger
authors.forename: Irena
authors.initials: I
authors.lastname: Jankowska
authors.forename: Joanna
authors.initials: J
authors.lastname: Pawlowska
authors.forename: Erica
authors.initials: E
authors.lastname: Villa
authors.forename: A S
authors.initials: AS
authors.lastname: Knisely
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Thompson
authors.forename: Nelson B
authors.initials: NB
authors.lastname: Freimer
authors.forename: Roderick H J
authors.initials: RH
authors.lastname: Houwen
authors.forename: Laura N
authors.initials: LN
authors.lastname: Bull
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D002779:Cholestasis / Q000235:genetics*; D005787:Gene Frequency; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D012008:Recurrence
chemical_list: D000251:Adenosine Triphosphatases; C111067:ATP8B1 protein, human