Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis.
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.
Papanikolaou
George
G
First Department of Internal Medicine, National and Kapodistrian University of Athens, School of Medicine, Laikon General Hospital, Athens 11527, Greece.
Samuels
Mark E
ME
Ludwig
Erwin H
EH
MacDonald
Marcia L E
ML
Franchini
Patrick L
PL
Dubé
Marie-Pierre
MP
Andres
Lisa
L
MacFarlane
Julie
J
Sakellaropoulos
Nikos
N
Politou
Marianna
M
Nemeth
Elizabeta
E
Thompson
Jay
J
Risler
Jenni K
JK
Zaborowska
Catherine
C
Babakaiff
Ryan
R
Radomski
Christopher C
CC
Pape
Terry D
TD
Davidas
Owen
O
Christakis
John
J
Brissot
Pierre
P
Lockitch
Gillian
G
Ganz
Tomas
T
Hayden
Michael R
MR
Goldberg
Y Paul
YP
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
D058851:GPI-Linked Proteins; C481006:HJV protein, human; D000071020:Hemochromatosis Protein; D008565:Membrane Proteins