Author(s): Victoria E. H. Carlton ; Baruch Z. Harris ; Erik G. Puffenberger ; A. K. Batta ; A. S. Knisely ; Donna L. Robinson ; Kevin A. Strauss ; Benjamin L. Shneider ; Wendell A. Lim ; Gerald Salen ; D. Holmes Morton ; Laura N. Bull (corresponding author) 
Familial hypercholanemia (FHC) is characterized by elevated serum bile acid concentrations, itching, and fat malabsorption [1, 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 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 .
We have identified 17 individuals with FHC in 12 families of Lancaster County Old Order Amish descent (Fig. 1; Table 1). Serum bile acid concentration in affected individuals fluctuated (often very high, occasionally normal). Fat malabsorption, reflecting low intestinal bile acid levels, was manifested by failure to thrive, potentially life-threatening vitamin-K dependent coagulopathy and rickets. Symptoms usually responded to treatment with ursodeoxycholic acid (UDCA). FHC is atypical for a liver disease: test results of biochemical markers of liver injury were normal, except for alkaline phosphatase activity, which sometimes rose. Liver biopsy findings varied. One untreated individual (1d) had canalicular cholestasis and two individuals (7c, 12c) receiving UDCA had minimally active chronic hepatitis . Several older individuals have become symptom-free and have discontinued UDCA treatment. We have no information on the natural history of FHC in adults.
A whole-genome screen identified one chromosomal region (9q12-q13) shared identically by descent (IBD) on most (6 of 10) chromosomes of affected individuals included in the initial analysis. Several 9q12-q13 markers were in linkage disequilibrium with FHC (Fig. 2a ). We examined the region in additional individuals with FHC. Of 12 individuals genotyped, 8 shared the haplotype in 9q12-q13 (Fig. 2 b ), a region containing the candidate gene TJP2 . Genomic sequencing of exons and exon-intron boundaries of TJP2 in individual 3c identified a mutation, 143T[right arrow]C, predicted to cause a valine-to-alanine substitution (V48A) in TJP2. Screening of all 17 individuals with FHC identified 11 individuals (including a pair of monozygotic twins) in 8 families who were homozygous with respect to the mutation (TJP2 143C/143C ; Table 1). Three unaffected siblings were also homozygous with respect to the mutation, showing that penentrance is incomplete. The mutation was not present in 190 control chromosomes from Caucasian individuals, 34 control chromosomes from Amish (non-Lancaster County) individuals or 15 non-transmitted parental chromosomes. It was seen on 7 of...
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