In a patient with benign recurrent intrahepatic cholestasis-1 (BRIC1; 243300), Bull et al. (1998) identified a 1982T-C transition in the ATP8B1 gene, resulting in an ile661-to-thr (I661T) amino acid substitution. The nonconservative mutation was at a site at which all members of the subfamily of P-type ATPases to which ATP8B1 belongs have a leucine or isoleucine residue. The mutation was present on the most common conserved haplotype in BRIC patients of western European descent. It was present in homozygous form in patients from 13 families and in heterozygous form in patients from 6 additional families, and was not found on 84 control chromosomes.
Tygstrup et al. (1999) identified homozygosity for the I661T mutation in 5 males with BRIC from the Faroe Islands who were originally reported by Tygstrup and Jensen (1969). Haplotype analysis suggested a founder effect.
Klomp et al. (2004) identified the I661T mutation in 14 BRIC families; 3 families were homozygous, 8 were compound heterozygous with another ATP8B1 mutation, and in 3 families a second mutation was not identified. Two families with progressive familial intrahepatic cholestasis (PFIC; 211600) were compound heterozygous for the I661T mutation and another ATP8B1 mutation. In 1 family with BRIC, 4 individuals who were homozygous for the I661T mutation were symptom-free their entire lives, suggesting reduced penetrance.
