Nature Genetics
36, 77 - 82 (2004)
Published online: 30 November 2003; | doi:10.1038/ng1274
Mutations in HFE2 cause iron overload in chromosome 1q−linked juvenile hemochromatosisGeorge Papanikolaou1, Mark E Samuels2, Erwin H Ludwig2, Marcia L E MacDonald2, Patrick L Franchini2, Marie-Pierre Dubé3, Lisa Andres2, Julie MacFarlane2, Nikos Sakellaropoulos1, Marianna Politou1, Elizabeta Nemeth4, Jay Thompson2, Jenni K Risler2, Catherine Zaborowska2, Ryan Babakaiff2, Christopher C Radomski2, Terry D Pape2, Owen Davidas2, John Christakis5, Pierre Brissot6, Gillian Lockitch7, Tomas Ganz4, Michael R Hayden2, 8
& Y Paul Goldberg2, 81
First Department of Internal Medicine, National and Kapodistrian University of Athens, School of Medicine, Laikon General Hospital, Athens 11527, Greece. 2
Xenon Genetics, Burnaby, British Columbia V5G 4W8, Canada. 3
Xenon Genetics Research, Montreal, Quebec H3A 1L2, Canada. 4
Department of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA. 5
Department of Hematology, Theagenio Cancer Center, Thessaloniki 54007, Greece. 6
Service Des Maladies du Foie & INSERM U-522, University of Rennes, Rennes 35033, France. 7
Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6H 3V4, Canada. 8
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada.
Correspondence should be addressed to Michael R Hayden mrh@cmmt.ubc.caJuvenile 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 metabolism7,
8,
9. 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.
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