title: A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis.
abstract: North American Indian childhood cirrhosis (CIRH1A, or NAIC), a severe autosomal recessive intrahepatic cholestasis described in Ojibway-Cree children from northwestern Quebec, is one of several familial cholestases with unknown molecular etiology. It typically presents with transient neonatal jaundice, in a child who is otherwise healthy, and progresses to biliary cirrhosis and portal hypertension. Clinical and physiological investigations have not revealed the underlying cause of the disease. Currently, liver transplantation is the only effective therapy for patients with advanced disease. We previously identified the NAIC locus by homozygosity mapping to chromosome 16q22. Here we report that an exon 15 mutation in gene FLJ14728 (alias Cirhin) causes NAIC: c.1741C-->T in GenBank cDNA sequence NM_032830, found in all NAIC chromosomes, changes the conserved arginine 565 codon to a tryptophan, altering the predicted secondary structure of the protein. Cirhin is preferentially expressed in embryonic liver, is predicted to localize to mitochondria, and contains WD repeats, which are structural motifs frequently associated with molecular scaffolds.
authors.affiliation: Division of Medical Genetics, Hôpital Ste-Justine, Centre Hospitalier Universitaire Mère-Enfant, Université de Montréal, Québec, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Chagnon
authors.forename: Jacques
authors.initials: J
authors.lastname: Michaud
authors.forename: Grant
authors.initials: G
authors.lastname: Mitchell
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Mercier
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Marion
authors.forename: Eric
authors.initials: E
authors.lastname: Drouin
authors.forename: Andrée
authors.initials: A
authors.lastname: Rasquin-Weber
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudson
authors.forename: Andrea
authors.initials: A
authors.lastname: Richter
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002648:Child; D002780:Cholestasis, Intrahepatic / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D017124:Conserved Sequence / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017403:In Situ Hybridization; D007198:Indians, North American / Q000235:genetics*; D008103:Liver Cirrhosis / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D017433:Protein Structure, Secondary; D011506:Proteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D011792:Quebec; D012261:Ribonucleoproteins; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics
chemical_list: D011506:Proteins; D012261:Ribonucleoproteins; D029701:Saccharomyces cerevisiae Proteins; C470475:UTP4 protein, human