title: Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis.
abstract: Juvenile hemochromatosis is an early-onset autosomal recessive disorder of iron overload resulting in cardiomyopathy, diabetes and hypogonadism that presents in the teens and early 20s (refs. 1,2). Juvenile hemochromatosis has previously been linked to the centromeric region of chromosome 1q (refs. 3-6), a region that is incomplete in the human genome assembly. Here we report the positional cloning of the locus associated with juvenile hemochromatosis and the identification of a new gene crucial to iron metabolism. We finely mapped the recombinant interval in families of Greek descent and identified multiple deleterious mutations in a transcription unit of previously unknown function (LOC148738), now called HFE2, whose protein product we call hemojuvelin. Analysis of Greek, Canadian and French families indicated that one mutation, the amino acid substitution G320V, was observed in all three populations and accounted for two-thirds of the mutations found. HFE2 transcript expression was restricted to liver, heart and skeletal muscle, similar to that of hepcidin, a key protein implicated in iron metabolism. Urinary hepcidin levels were depressed in individuals with juvenile hemochromatosis, suggesting that hemojuvelin is probably not the hepcidin receptor. Rather, HFE2 seems to modulate hepcidin expression.
authors.affiliation: First Department of Internal Medicine, National and Kapodistrian University of Athens, School of Medicine, Laikon General Hospital, Athens 11527, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Papanikolaou
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
authors.forename: Erwin H
authors.initials: EH
authors.lastname: Ludwig
authors.forename: Marcia L E
authors.initials: ML
authors.lastname: MacDonald
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Franchini
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.forename: Lisa
authors.initials: L
authors.lastname: Andres
authors.forename: Julie
authors.initials: J
authors.lastname: MacFarlane
authors.forename: Nikos
authors.initials: N
authors.lastname: Sakellaropoulos
authors.forename: Marianna
authors.initials: M
authors.lastname: Politou
authors.forename: Elizabeta
authors.initials: E
authors.lastname: Nemeth
authors.forename: Jay
authors.initials: J
authors.lastname: Thompson
authors.forename: Jenni K
authors.initials: JK
authors.lastname: Risler
authors.forename: Catherine
authors.initials: C
authors.lastname: Zaborowska
authors.forename: Ryan
authors.initials: R
authors.lastname: Babakaiff
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Radomski
authors.forename: Terry D
authors.initials: TD
authors.lastname: Pape
authors.forename: Owen
authors.initials: O
authors.lastname: Davidas
authors.forename: John
authors.initials: J
authors.lastname: Christakis
authors.forename: Pierre
authors.initials: P
authors.lastname: Brissot
authors.forename: Gillian
authors.initials: G
authors.lastname: Lockitch
authors.forename: Tomas
authors.initials: T
authors.lastname: Ganz
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Y Paul
authors.initials: YP
authors.lastname: Goldberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002878:Chromosomes, Human, Pair 1; D058851:GPI-Linked Proteins; D006432:Hemochromatosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D006801:Humans; D019190:Iron Overload; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics
chemical_list: D058851:GPI-Linked Proteins; C481006:HJV protein, human; D000071020:Hemochromatosis Protein; D008565:Membrane Proteins