Hypercholanemia, Familial

A number sign (#) is used with this entry because of evidence that hypercholanemia can be caused by homozygous mutation in the TJP2 gene (607709) on chromosome 9q21 or by the BAAT gene (602938) on chromosome 9q31. One patient has been reported with compound heterozygous mutation in the EPHX1 gene (132810) on chromosome 1q42.

Clinical Features

Familial hypercholanemia is characterized by elevated serum bile acid concentrations, itching, and fat malabsorption (Morton et al., 2000; Shneider et al., 1997). Carlton et al. (2003) identified 17 individuals with familial hypercholanemia in 12 families of Lancaster County Old Order Amish descent. Serum bile acid concentration in affected individuals fluctuated, being often very high but occasionally normal. Fat malabsorption, reflecting low intestinal bile acid levels, manifested by failure to thrive, potentially life-threatening vitamin K-dependent coagulopathy, and rickets. Symptoms usually responded to treatment with ursodeoxycholic acid (UDCA). Familial hypercholanemia 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; 1 untreated individual had canalicular cholestasis and 2 individuals receiving UDCA had minimally active chronic hepatitis. Several older individuals had become symptom-free and discontinued UDCA treatment.

Molecular Genetics

By whole-genome screen, Carlton et al. (2003) identified a chromosomal region, 9q12-q13, shared identically by descent (IBD) on 6 of 10 chromosomes of affected individuals included in the initial analysis. The gene encoding tight junction protein-2 (TJP2; 607709) lies within the 9q12-q13 region. Genomic sequencing of exons and exon-intron boundaries of TJP2 in 1 affected individual identified a val48-to-ala mutation in TJP2 (V48A; 607709.0001). Screening of all 17 individuals with familial hypercholanemia showed that 11 (including a pair of monozygotic twins) in 8 families were homozygous with respect to the V48A mutation. Three unaffected sibs were also homozygous, showing that penetrance was incomplete. The mutation was not present in 190 control chromosomes from Caucasian individuals. It was seen on 7 of 104 control chromosomes from Lancaster County Old Order Amish individuals.

In 4 individuals with familial hypercholanemia who did not have the TJP2 V48A mutation, Carlton et al. (2003) identified an IBD haplotype in 9q22-q32, a region containing the candidate gene BAAT (602938). Genomic sequencing of exons and exon-intron boundaries of BAAT in 1 individual identified a met76-to-val (M76V; 602938.0001) mutation. Screening of all 17 individuals with hypercholanemia identified 5 individuals (in 3 families) who were homozygous with respect to this mutation. Several individuals who were homozygous for the TJP2 V48A mutation were also heterozygous for the BAAT M76V mutation. The BAAT mutation was not seen in 182 control chromosomes from Caucasian subjects and was seen in only 1 of 104 control chromosomes from Lancaster County Old Order Amish individuals.

Carlton et al. (2003) found 1 individual with familial hypercholanemia who did not have either mutation (TJP2 V48A or BAAT M76V) and was not homozygous in either region on chromosome 9. That several individuals carried mutations in both genes suggested oligogenic inheritance.

In a patient with hypercholanemia, Zhu et al. (2003) identified compound heterozygosity for 2 mutations in the EPHX1 gene (see 132810.0003), which resulted in a significant decrease in EPHX1 promoter activity.

Pathogenesis

Carlton et al. (2003) postulated that in individuals homozygous for the BAAT M76V mutation, bile acids do not traverse hepatocytes into bile. In contrast, they believed that in individuals homozygous for the TJP2 V48A mutation, bile acids enter bile and then leak through tight junctions into plasma.

Nomenclature

Carlton et al. (2003) used FHC as the symbol for familial hypercholanemia. This is an unfortunate and potentially confusing usage since FHC has a long track record as the abbreviation for familial hypercholesterolemia (143890).