Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT.
Carlton VE,
Harris BZ,
Puffenberger EG,
Batta AK,
Knisely AS,
Robinson DL,
Strauss KA,
Shneider BL,
Lim WA,
Salen G,
Morton DH,
Bull LN.
Liver Center Laboratory and Department of Medicine, San Francisco General Hospital, University of California San Francisco, California 94110, USA.
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.
PMID: 12704386 [PubMed - indexed for MEDLINE]