The Hemochromatosis Founder Mutation in HLA-H Disrupts β2-Microglobulin Interaction and Cell Surface Expression*

@article{Feder1997TheHF,
  title={The Hemochromatosis Founder Mutation in HLA-H Disrupts $\beta$2-Microglobulin Interaction and Cell Surface Expression*},
  author={John N. Feder and Zenta Tsuchihashi and Alivelu Irrinki and Victor K. Lee and Felipa A Mapa and E Morikang and C E Prass and S M Starnes and Roger K Wolff and Seppo Parkkila and William S. Sly and Randall C. Schatzman},
  journal={The Journal of Biological Chemistry},
  year={1997},
  volume={272},
  pages={14025 - 14028}
}
We recently reported the positional cloning of a candidate gene for hereditary hemochromatosis (HH), calledHLA-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… Expand
Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells.
  • A. Waheed, S. Parkkila, +7 authors W. Sly
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 1997
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 majorExpand
The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.
TLDR
A molecular link between HFE and a key protein involved in iron transport, the TfR, is established and the possibility that alterations in this regulatory mechanism may play a role in the pathogenesis of hereditary hemochromatosis is raised. Expand
The haemochromatosis protein HFE induces an apparent iron-deficient phenotype in H1299 cells that is not corrected by co-expression of beta 2-microglobulin.
TLDR
Clones of human H1299 lung cancer cells that express wild-type, C282Y or H63D HFE under the control of a tetracycline-inducible promoter suggest that the apparent iron-deficient phenotype elicited by HFE is not linked to beta(2)M insufficiency. Expand
Hemochromatosis: a genetic defect in iron metabolism
  • E. Jazwinska
  • Biology, Medicine
  • BioEssays : news and reviews in molecular, cellular and developmental biology
  • 1998
TLDR
The first important step toward establishing the role of HFE in the pathogenesis of HC came with the recent observation that the C282Y mutation disrupts the binding of β2‐microglobulin to the HFE protein and as a result the mutant molecule is not expressed on the cell surface. Expand
Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis.
  • S. Parkkila, A. Waheed, +5 authors W. Sly
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 1997
TLDR
It is demonstrated 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. Expand
A novel mutation of HFE explains the classical phenotype of genetic hemochromatosis in a C282Y heterozygote.
TLDR
The demonstration of IVS3 +1G --> T in the compound heterozygous state with C282Y results in iron overload that can progress to a severe phenotype of classical hemochromatosis, and highlights the possibility of other rare HFE mutations, particularly in C282y heterozygotes with iron overload. Expand
The hemochromatosis 845 G-->A and 187 C-->G mutations: prevalence in non-Caucasian populations.
TLDR
The present study used PCR and restriction-enzyme digestion to analyze the frequency of the 845 G-->A and 187 C-->G mutations in HLA-typed samples from non-Caucasian populations, comprising Australian Aboriginal, Chinese, and Pacific Islanders, and showed that the 8 45 G -->A mutation was present in these populations (allele frequency 0.32%) and was always seen in conjunction with HLA haplotypes common in Caucasians. Expand
Haemochromatosis: an inherited metal and toxicity syndrome.
  • T. Cox, A. Kelly
  • Biology, Medicine
  • Current opinion in genetics & development
  • 1998
TLDR
A newly-identified major histocompatibility Class I-like gene, HFE (originally HLA-H), located approximately 3.5 Mb telomeric to the Class I cluster on chromosome 6p 21.3 harbours mutations in haemochromatosis and interacts with the transferrin-receptor, affecting receptor turnover or its affinity for ligand. Expand
Over‐expression of wild‐type and mutant HFE in a human melanocytic cell line reveals an intracellular bridge between MHC class I pathway and transferrin iron uptake
TLDR
A stably over‐expressed wild type and mutated forms fused to the Green Fluorescent Protein in a melanocytic MHC class I expressing cell line, the Mel Juso cell line will be of use in the elucidation of the functional interaction between intracellular HFE and iron transporters transferrin/transferrin receptor complexes and Slc11A2 in different endosomal compartments. Expand
HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis.
TLDR
The results confirm that the C282Y substitution was the main mutation involved in hemochromatosis, accounting for 85% of carrier chromosomes, whereas the H63D substitution represented 39% of the HH chromosomes that did not carry the C283Y mutation, and showed that the S65C substitution was significantly enriched in probands with at least one chromosome without an assigned mutation. Expand
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