title: A missense mutation in FIC1 is associated with greenland familial cholestasis.
abstract: Greenland familial cholestasis is a severe form of intrahepatic cholestasis described among indigenous Inuit families in Greenland. Patients present with jaundice, pruritus, bleeding episodes, and steatorrhea, and die in childhood due to end-stage liver disease. We investigated the possibility that Greenland familial cholestasis is caused by a mutation in FIC1, the gene defective in patients with progressive familial intrahepatic cholestasis type 1 and many cases of benign recurrent intrahepatic cholestasis. Using single-strand conformation polymorphism analysis and sequencing of the FIC1 exons, a missense mutation, 1660 G-->A (D554N), was detected and was shown to segregate with the disease in Inuit patients from Greenland and Canada. Examination of liver specimens from 3 Inuit patients homozygous for this mutation revealed bland canalicular cholestasis and, on transmission electron microscopy, coarsely granular Byler bile, as previously described in patients with progressive familial intrahepatic cholestasis type 1. These data establish Greenland familial cholestasis as a form of progressive familial intrahepatic cholestasis type 1 and further underscore the importance of unimpeded FIC1 activity for normal bile formation.
authors.affiliation: Department of Pediatric Gastroenterology, University Medical Center, Utrecht, The Netherlands.
authors.forename: L W
authors.initials: LW
authors.lastname: Klomp
authors.forename: L N
authors.initials: LN
authors.lastname: Bull
authors.forename: A S
authors.initials: AS
authors.lastname: Knisely
authors.forename: M A
authors.initials: MA
authors.lastname: van Der Doelen
authors.forename: J A
authors.initials: JA
authors.lastname: Juijn
authors.forename: R
authors.initials: R
authors.lastname: Berger
authors.forename: S
authors.initials: S
authors.lastname: Forget
authors.forename: I M
authors.initials: IM
authors.lastname: Nielsen
authors.forename: H
authors.initials: H
authors.lastname: Eiberg
authors.forename: R H
authors.initials: RH
authors.lastname: Houwen
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D002648:Child; D002779:Cholestasis / Q000235:genetics* / Q000473:pathology; D005260:Female; D006116:Greenland; D006720:Homozygote; D006801:Humans; D004930:Inuit / Q000235:genetics; D008099:Liver / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D020125:Mutation, Missense; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D012326:RNA Splicing
chemical_list: D000251:Adenosine Triphosphatases; C111067:ATP8B1 protein, human