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.
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Hepcidin production is diminished in juvenile hemochromatosis due to mutations in the hemojuvelin gene.
“Hepcidin production was also diminished in another form of juvenile hemochromatosis due to mutations in the hemojuvelin gene”
From IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin (2004) · cites this paper as [10]
In yeast, frataxin is involved in mitochondrial iron efflux or iron storage.
“In yeast, it was demonstrated that frataxin is involved in mitochondrial iron efflux (252) or iron storage (96, 234).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [234]
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- Authors
- Papanikolaou, G., Samuels, M. E., Ludwig, E. H., MacDonald, M. L. E., Franchini, P. L., Dubé, M.-P., Andres, L., MacFarlane, J., Sakellaropoulos, N., Politou, M., Nemeth, E., Thompson, J., Risler, J. K., Zaborowska, C., Babakaiff, R., Radomski, C. C., Pape, T. D., Davidas, O., Christakis, J., Brissot, P., Lockitch, G., Ganz, T., Hayden, M. R., & Goldberg, Y. P.
- Affiliations
- National and Kapodistrian University of Athens (GR)
- University of California, Los Angeles (US)
- Theageneio General Hospital (GR)
- Inserm (FR)
- University of British Columbia (CA)
- Corresponding author
- Hayden, Michael R
- ORCID
- Venue
- Nature Genetics
- Published
- 2003-11-30
- Volume
- 36
- Issue
- 1
- Pages
- 77-82
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2116064842
- Cited by
- 974
- References
- 29
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 12 · 2023: 14 · 2022: 13 · 2021: 27 · 2020: 23 · 2019: 20 · 2018: 31 · 2017: 44 · 2016: 32 · 2015: 35 · 2014: 32 · 2013: 47 · 2012: 55
- FWCI
- 35.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- BC Children's Hospital
- National and Kapodistrian University of Athens
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- juvenile hemochromatosis, hemojuvelin, iron overload, chromosome 1q, positional cloning, iron metabolism, hepcidin, autosomal recessive disorder
- MeSH terms
- Hemochromatosis Protein, Adolescent, Adult, Amino Acid Sequence, Base Sequence, Child, Chromosomes, Human, Pair 1, Hemochromatosis, Humans, Membrane Proteins, Middle Aged, Molecular Sequence Data, Mutation, Iron Overload, GPI-Linked Proteins
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