title: Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT.
abstract: Familial hypercholanemia (FHC) is characterized by elevated serum bile acid concentrations, itching, and fat malabsorption. We show here that FHC in Amish individuals is associated with mutations in tight junction protein 2 (encoded by TJP2, also known as ZO-2) and bile acid Coenzyme A: amino acid N-acyltransferase (encoded by BAAT). The mutation of TJP2, which occurs in the first PDZ domain, reduces domain stability and ligand binding in vitro. We noted a morphological change in hepatic tight junctions. The mutation of BAAT, a bile acid-conjugating enzyme, abrogates enzyme activity; serum of individuals homozygous with respect to this mutation contains only unconjugated bile acids. Mutations in both TJP2 and BAAT may disrupt bile acid transport and circulation. Inheritance seems to be oligogenic, with genotype at BAAT modifying penetrance in individuals homozygous with respect to the mutation in TJP2.
authors.affiliation: Liver Center Laboratory and Department of Medicine, San Francisco General Hospital, University of California San Francisco, California 94110, USA.
authors.forename: Victoria E H
authors.initials: VE
authors.lastname: Carlton
authors.forename: Baruch Z
authors.initials: BZ
authors.lastname: Harris
authors.forename: Erik G
authors.initials: EG
authors.lastname: Puffenberger
authors.forename: A K
authors.initials: AK
authors.lastname: Batta
authors.forename: A S
authors.initials: AS
authors.lastname: Knisely
authors.forename: Donna L
authors.initials: DL
authors.lastname: Robinson
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Strauss
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Shneider
authors.forename: Wendell A
authors.initials: WA
authors.lastname: Lim
authors.forename: Gerald
authors.initials: G
authors.lastname: Salen
authors.forename: D Holmes
authors.initials: DH
authors.lastname: Morton
authors.forename: Laura N
authors.initials: LN
authors.lastname: Bull
mesh_terms: D000217:Acyltransferases / Q000235:genetics*; D001647:Bile Acids and Salts / Q000097:blood*; D016022:Case-Control Studies; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008099:Liver / Q000473:pathology; D008286:Malabsorption Syndromes / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010414:Pennsylvania; D010641:Phenotype; D019108:Tight Junctions / Q000473:pathology; D062827:Zonula Occludens-2 Protein
chemical_list: D001647:Bile Acids and Salts; D008565:Membrane Proteins; C569046:TJP2 protein, human; D062827:Zonula Occludens-2 Protein; D000217:Acyltransferases; C026953:bile acid-CoA amino acid N-acyltransferase