A missense mutation in FIC1 is associated with Greenland familial cholestasis

Greenland familial cholestasis is a severe form of intrahepatic cholestasis described among indigenous Inuit families in Greenland. Patients present w ith jaundice, pruritus, bleeding episodes, and steatorrhea, and die in chil dhood due to end-stage liver disease. We investigated the possibility that Greenland familial cholestasis is caused by a mutation in FIC1, the gene de fective in patients with progressive familial intrahepatic cholestasis type 1 and many cases of benign recurrent intrahepatic cholestasis. Using singl e-strand conformation polymorphism analysis and sequencing of the FIC1 exon s, a missense mutation, 1660 G-->A (D554N), was detected and was shown to s egregate with the disease in Inuit patients from Greenland and Canada. Exam ination of liver specimens from 3 Inuit patients homozygous for this mutati on revealed bland canalicular cholestasis and, on transmission electron mic roscopy, coarsely granular Byler bile, as previously described in patients with progressive familial intrahepatic cholestasis type 1. These data estab lish Greenland familial cholestasis as a form of progressive familial intra hepatic cholestasis type 1 and further underscore the importance of unimped ed FIC1 activity for normal bile formation.