Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with β 2 -microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells
Open accessAbstract
Hereditary hemochromatosis (HH) is the most common autosomal recessive disorder known in humans. A candidate gene for HH called HFE has recently been cloned that encodes a novel member of the major histocompatibility complex class I family. Most HH patients are homozygous for a Cys-282→Tyr (C282Y) mutation in HFE gene, which has been shown to disrupt interaction with β 2 -microglobulin; a second mutation, His-63→Asp (H63D), is enriched in HH patients who are heterozygous for C282Y mutation. The aims of this study were to determine the effects of the C282Y and H63D mutations on the cellular trafficking and degradation of the HFE protein in transfected COS-7 cells. The results indicate that, while the wild-type and H63D HFE proteins associate with β 2 -microglobulin and are expressed on the cell surface of COS-7 cells, these capabilities are lost by the C282Y HFE protein. We present biochemical and immunofluorescence data that indicate that the C282Y mutant protein: ( i ) is retained in the endoplasmic reticulum and middle Golgi compartment, ( ii ) fails to undergo late Golgi processing, and ( iii ) is subject to accelerated degradation. The block in intracellular transport, accelerated turnover, and failure of the C282Y protein to be presented normally on the cell surface provide a possible basis for impaired function of this mutant protein in HH.
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The increased susceptibility of FRDA patient cells to iron-mediated cytotoxicity and hydrogen peroxide was rescued by treatment with deferoxamine or by near-physiologic levels of frataxin expression.
“which was rescued by treatment with the iron chelator deferoxamine (321) or by near-physiologic levels of frataxin expression (287).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [321]
Cells derived from FRDA patients contained a 40% increase in mitochondrial iron content and were more susceptible to iron-mediated cytotoxicity and hydrogen peroxide.
“Similarly, cells derived from FRDA patients contained 40% increase in mitochondrial iron content and were more susceptible to iron-mediated cytotoxicity and hydrogen peroxide (287, 321)”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [321]
The iron chelator deferoxamine protects FRDA fibroblasts from H2O2-induced cytotoxicity.
“The iron chelator deferoxamine was shown to protect FRDA fibroblasts from H2O2-induced cytotoxicity (321).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [321]
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- Authors
- Waheed, A., Parkkila, S., Zhou, X. Y., Tomatsu, S., Tsuchihashi, Z., Feder, J. N., Schatzman, R. C., Britton, R. S., Bacon, B. R., & Sly, W. S.
- Affiliations
- Edward A. Doisy Department of Biochemistry and Molecular Biology, and Division of Gastroenterology and Hepatology, Department of Internal Medicine, 1402 South Grand Boulevard, Saint Louis University School of Medicine, St. Louis, MO 63104; and Mercator Genetics, Inc., Menlo Park, CA 94025
- Saint Louis University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1997-11-11
- Volume
- 94
- Issue
- 23
- Pages
- 12384-12389
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC24956
- OpenAlex
- W2080638597
- Cited by
- 380
- References
- 33
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 4 · 2022: 2 · 2021: 6 · 2020: 5 · 2019: 4 · 2018: 3 · 2017: 9 · 2016: 18 · 2015: 11 · 2014: 11 · 2013: 6 · 2012: 7
- FWCI
- 14.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (GM34182)
- National Institute of General Medical Sciences (GM34182, R01GM034182)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK041816, DK 41816, DK-40163, R01DK040163)
- 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, C282Y mutation, H63D mutation, beta2-microglobulin, protein trafficking, endoplasmic reticulum retention, Golgi processing, protein degradation, cell surface expression, MHC class I, COS-7 cells
- MeSH terms
- Hemochromatosis Protein, Animals, beta 2-Microglobulin, Biological Transport, Gene Expression Regulation, Hemochromatosis, HLA Antigens, Membrane Proteins, Mutation, Histocompatibility Antigens Class I, COS Cells
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