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(Received for publication, March 12, 1997, and in revised form, March 15, 1997)
From 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
Volume 272, Number 22,
Issue of May 30, 1997
pp. 14025-14028
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
COMMUNICATION:
2-Microglobulin Interaction and Cell Surface
Expression
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Mercator Genetics, Inc., Menlo Park,
California 94025 and the § Edward H. Doisy Department of
Biochemistry and Molecular Biology, Saint Louis University School
of Medicine, St. Louis, Missouri 63104
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 
2-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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S Distante, J P Berg, K Lande, E Haug, and H Bell HFE gene mutation (C282Y) and phenotypic expression among a hospitalised population in a high prevalence area of haemochromatosis Gut, October 1, 2000; 47(4): 575 - 579. [Abstract] [Full Text] [PDF]
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 W.J.H. Griffiths, A.L. Kelly, S.J. Smith, and T.M. Cox Localization of iron transport and regulatory proteins in human cells QJM, September 1, 2000; 93(9): 575 - 587. [Abstract] [Full Text] [PDF]
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