Abstract
Familial hypercholanemia (FHC) is characterized by elevated serum bile acid concentrations, itching, and fat malabsorption1,2. 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-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 enzyme3, 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.
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Acknowledgements
The authors thank the individuals with FHC and their family members for their participation; I. Herskowitz for support and contributions; S. Service for software and advice; C. Hendrickson, J. Doherty, J. Woo, H. Yoon, E. Song, J. Vargas, R. Senkus, M. Maksimak, E. Cunningham, D. Agard, A. Frankel, V. Calabro, K. Novak and R. K. Guy for advice, assistance and the use of equipment; and N. Risch, N. Freimer, C. Slates, W. Hsueh, A. Slavotinek, R. Kelley and F. Collins for discussions. This work was supported by grants from the US National Institutes of Health, the Howard Hughes Medical Institute, the University of California San Francisco Program in Human Genetics and the Tetrad Graduate Program.
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Carlton, V., Harris, B., Puffenberger, E. et al. Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT. Nat Genet 34, 91–96 (2003). https://doi.org/10.1038/ng1147
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DOI: https://doi.org/10.1038/ng1147
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