Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis
Open accessAbstract
Hereditary hemochromatosis (HH) is a common autosomal recessive disease associated with loss of regulation of dietary iron absorption and excessive iron deposition in major organs of the body. Recently, a candidate gene for HH (also called HFE) was identified that encodes a novel MHC class I-like protein. Most patients with HH are homozygous for the same mutation in the HFE gene, resulting in a C282Y change in the HFE protein. Studies in cultured cells show that the C282Y mutation abrogates the binding of the recombinant HFE protein to β 2 -microglobulin (β 2 M) and disrupts its transport to the cell surface. The HFE protein was shown by immunohistochemistry to be expressed in certain epithelial cells throughout the human alimentary tract and to have a unique localization in the cryptal cells of small intestine, where signals to regulate iron absorption are received from the body. In the studies presented here, we demonstrate by immunohistochemistry that the HFE protein is expressed in human placenta in the apical plasma membrane of the syncytiotrophoblasts, where the transferrin-bound iron is normally transported to the fetus via receptor-mediated endocytosis. Western blot analyses show that the HFE protein is associated with β 2 M in placental membranes. Unexpectedly, the transferrin receptor was also found to be associated with the HFE protein/β 2 M complex. These studies place the normal HFE protein at the site of contact with the maternal circulation where its association with transferrin receptor raises the possibility that the HFE protein plays some role in determining maternal/fetal iron homeostasis. These findings also raise the question of whether mutations in the HFE gene can disrupt this association and thereby contribute to some forms of neonatal iron overload.
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Cells derived from the cerebellum of neonatal Cp-knockout mice are more sensitive to oxidative stress in vitro.
“Cells derived from the cerebellum of neonatal Cp-knockout mice were more sensitive to oxidative stress in vitro (239).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [239]
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- Authors
- Parkkila, S., Waheed, A., Britton, R. S., Bacon, B. R., Zhou, X. Y., Tomatsu, S., Fleming, R. E., & Sly, W. S.
- Affiliations
- Saint Louis University (US)
- The Edward A. Doisy Department of Biochemistry and Molecular Biology, and Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO 63104
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1997-11-25
- Volume
- 94
- Issue
- 24
- Pages
- 13198-13202
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC24286
- OpenAlex
- W2147487590
- Cited by
- 336
- References
- 28
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2018: 2 · 2017: 5 · 2016: 8 · 2015: 3 · 2014: 5 · 2013: 7 · 2012: 4
- FWCI
- 18.26
- 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 › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- HFE gene, hereditary hemochromatosis, transferrin receptor, placenta, syncytiotrophoblast, beta2-microglobulin, iron transport, C282Y mutation, iron absorption regulation
- MeSH terms
- Hemochromatosis Protein, beta 2-Microglobulin, Chromatography, Affinity, Female, Hemochromatosis, HLA Antigens, Humans, Immunohistochemistry, Membrane Proteins, Placenta, Precipitin Tests, Pregnancy, Protein Binding, Receptors, Transferrin, Histocompatibility Antigens Class I
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