The Hemochromatosis Founder Mutation in HLA-H Disrupts β2-Microglobulin Interaction and Cell Surface Expression
Open accessAbstract
We recently reported the positional cloning of a candidate gene for hereditary hemochromatosis (HH), called HLA-H, which is a novel member of the major histocompatibility complex class I family. A mutation in this gene, cysteine 282 --> tyrosine (C282Y), was found to be present in 83% of HH patient DNAs, while a second variant, histidine 63 --> aspartate (H63D), was enriched in patients heterozygous for C282Y. The functional relevance of either mutation has not been described. Co-immunoprecipitation studies of cell lysates from human embryonic kidney cells transfected with wild-type or mutant HLA-H cDNA demonstrate that wild-type HLA-H binds beta2-microglobulin and that the C282Y mutation, but not the H63D mutation, completely abrogates this interaction. Immunofluorescence labeling and subcellular fractionations demonstrate that while the wild-type and H63D HLA-H proteins are expressed on the cell surface, the C282Y mutant protein is localized exclusively intracellularly. This report describes the first functional significance of the C282Y mutation by suggesting that an abnormality in protein trafficking and/or cell-surface expression of HLA-H leads to HH disease.
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None of the ferritin H-deficient mice survived past embryonic day 9.5.
“None of the ferritin H-deficient mice survived past embryonic day 9.5 (85).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [85]
Ferritin H-deficient mice synthesize ferritins consisting of only L-subunit homopolymers, which lack ferroxidase activity and have lower iron-incorporation capability.
“the synthesized ferritins consist of only L-subunit homopolymers (85), which lack ferroxidase activity and has lower iron-incorporation capability (183).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [85]
Deletion of ferritin H in mice is embryonically lethal between 3.5 and 9.5 days of gestation.
“Deletion of ferritin H in mice is embryonically lethal between 3.5 and 9.5 days of gestation (85).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [85]
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- Authors
- Feder, J. N., Tsuchihashi, Z., Irrinki, A., Lee, V. K., Mapa, F. A., Morikang, E., Prass, C. E., Starnes, S. M., Wolff, R. K., Parkkila, S., Sly, W. S., & Schatzman, R. C.
- Affiliations
- Saint Louis University (US)
- Corresponding author
- Schatzman, Randall C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1997-05
- Volume
- 272
- Issue
- 22
- Pages
- 14025-14028
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2143716524
- Cited by
- 471
- References
- 21
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 6 · 2020: 5 · 2019: 1 · 2018: 6 · 2017: 10 · 2016: 14 · 2015: 5 · 2014: 9 · 2013: 12 · 2012: 15
- FWCI
- 22.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- 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
- hereditary hemochromatosis, HLA-H, HFE gene, C282Y mutation, H63D mutation, beta2-microglobulin, protein-protein interaction, cell surface expression, intracellular retention, protein trafficking, MHC class I, positional cloning
- MeSH terms
- Hemochromatosis Protein, Base Sequence, beta 2-Microglobulin, Cell Membrane, Gene Expression Regulation, Hemochromatosis, HLA Antigens, Humans, Membrane Proteins, Molecular Sequence Data, Mutation, Histocompatibility Antigens Class I
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