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 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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Acknowledgements
We thank P. Panayiotidis and S. P. Dourakis for collecting samples from affected individuals, N. Grewal and J. Wong for technical assistance, G. Gingera for administrative support and the families for their participation in this work. This work was supported in part by grants from the University of Athens (N.S.), the BC Children's Hospital New Research Fund (G.L.), the Will Rogers Fund (T.G.), the Research Supporting Section of the Municipality of Thessaloniki (J.C.) and the Association Fer et Foie (P.B.). M.R.H. holds a Canada Research Chair in Human Genetics.
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Portions of this research were financially supported by Xenon Genetics, either directly (through research collaborations) or indirectly (as some of the authors are Xenon employees).
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Papanikolaou, G., Samuels, M., Ludwig, E. et al. Mutations in HFE2 cause iron overload in chromosome 1q–linked juvenile hemochromatosis. Nat Genet 36, 77–82 (2004). https://doi.org/10.1038/ng1274
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DOI: https://doi.org/10.1038/ng1274
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