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- Title
Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT.
- Authors
Carlton, Victoria E. H.; Harris, Baruch Z.; Puffenberger, Erik G.; Batta, A. K.; Knisely, A. S.; Robinson, Donna L.; Strauss, Kevin A.; Shneider, Benjamin L.; Lim, Wendell A.; Salen, Gerald; Morton, D Holmes; Bull, Laura N.
- Abstract
Familial hypercholanemia (FHC) is characterized by elevated serum bile acid concentrations, itching, and fat malabsorption[SUP1,2]. 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-acyl-transferase (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[SUP3], abrogates enzyme activity; serum of individuals homozygous with respect to this mutation contains only unconjugated bile acids. Mutations in bothTJP2 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 inTJP2.
- Subjects
SERUM; AMINO acids; GENETIC polymorphisms; TIGHT junctions; GENETIC research; ENZYMES
- Publication
Nature Genetics, 2003, Vol 34, Issue 1, p91
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng1147