A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis

  title={A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis},
  author={John N. Feder and Andreas Gnirke and W. Thomas and Zenta Tsuchihashi and David A. Ruddy and A Basava and Farid Dormishian and Rosario Domingo and Michael C. Ellis and A. Fullan and Lyn Hinton and N Jones and B. Kimmel and Gregory S. Kronmal and Peter Lauer and Victor K. Lee and Deborah Loeb and Felipa A Mapa and Erin E. McClelland and Nicole C. Meyer and Gabriel A. Mintier and N. Moeller and T L Moore and Ebenezer Morikang and C E Prass and L Quintana and S M Starnes and Randall C. Schatzman and Karen J. Brunke and Dennis Drayna and Neil Risch and Bruce R. Bacon and Roger K Wolff},
  journal={Nature Genetics},
Hereditary haemochromatosis (HH), which affects some 1 in 400 and has an estimated carrier frequency of 1 in 10 individuals of Northern European descent, results in multi–organ dysfunction caused by increased iron deposition, and is treatable if detected early. Using linkage–disequilibrium and full haplotype analysis, we have identified a 250–kilobase region more than 3 megabases telomeric of the major histocompatibility complex (MHC) that is identical–by–descent in 85% of patient chromosomes… 

Mutations in the MHC class I-like candidate gene for hemochromatosis in French patients

The detection of 845A homozygosity should now permit diagnosis of a readily curable disease and the prevention of sometimes deadly complications in at least 72% of the patients.

Mutation analysis of the HLA-H gene in Italian hemochromatosis patients.

It is reported that the Cys282Tyr change accounts for 69% of HH chromosomes in a series of 75 unrelated Italian patients who fulfilled well-defined criteria for HH diagnosis, suggesting that in Italy the disease is more heterogeneous than reported in northern Europe.

Effects of Highly Conserved Major Histocompatibility Complex (MHC) Extended Haplotypes on Iron and Low CD8+ T Lymphocyte Phenotypes in HFE C282Y Homozygous Hemochromatosis Patients from Three Geographically Distant Areas

Interestingly, the association between A-A-T and CD8+ T-lymphocytes, which was confirmed in Porto and Alabama patients, was not observed in Nord-Trøndelag patients, showing that common HLA haplotypes like A*01-B*08 or A*03–B*07 segregating with HFE/C282Y in the three populations may carry different messages.

Haemochromatosis and HLA–H

Some of the uncertainty surrounding the role of HLA-H in HH may be resolved by the identification of complete concordance of the C282Y mutation (or some other mutation) in HLA H with disease status in HH families.

Frequency of the HFE gene mutations in five Italian populations.

Data from this study are consistent with the hypothesis that the C282Y mutation occurred in Caucasian populations of Celtic origin, whereas the H63D mutation is more ancient as demonstrated by the ubiquitous distribution.

Immunohistochemistry of HLA-H, the protein defective in patients with hereditary hemochromatosis, reveals unique pattern of expression in gastrointestinal tract.

  • S. ParkkilaA. Waheed W. Sly
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1997
It is shown that the HLA-H protein not only varies in its pattern of expression along the cranial/caudal axis of the gastrointestinal tract but that it has a unique subcellular localization in the crypts of the small intestine in proximity to the presumed sites of iron absorption.

The hereditary hemochromatosis gene (HFE)

  • J. Feder
  • Medicine, Biology
    Immunologic research
  • 1999
With the identification of the transferrin receptor as a protein capable of interacting with HFE, the authors are now beginning to understand how a protein with the structural characteristics of an MHC class I molecule can influence cellular iron homeostasis.

Improved molecular diagnosis of hereditary hemochromatosis using a DNA enzyme immunoassay.

A PCR-based method that uses a DNA enzyme immunoassay (DEIA) for the specific detection of C282Y mutations is described, which has been observed in the majority of HH patients.

Global prevalence of putative haemochromatosis mutations.

The distribution of the C282Y mutation coincides with that of populations in which haemochromatosis has been reported and is consistent with the theory of a north European origin for the mutation.



Linkage analysis of 6p21 polymorphic markers and the hereditary hemochromatosis: localization of the gene centromeric to HLA-F.

A linkage analysis of the disease locus was performed in a series of Italian hemochromatosis families to better define the HFE gene location with respect to HLA-class I A and F loci.

Haplotype analysis in Australian hemochromatosis patients: evidence for a predominant ancestral haplotype exclusively associated with hemochromatosis.

Haplotype analysis in Australian HC patients provides strong evidence for (a) the introduction of HC into this population on an ancestral haplotype, (b) a common mutation associated with HC in Australian patients, and (c) a candidate HC-gene region extending between and including D 6S248 and D6S105.

Evidence that the ancestral haplotype in Australian hemochromatosis patients may be associated with a common mutation in the gene.

Clinical evidence that the predominant ancestral haplotype in Australian patients is associated with a common mutation in the gene for Hemochromatosis is looked for and the high population frequency of the HC gene may be the result of the selective advantage conferred by protecting heterozygotes against iron deficiency.

beta2 knockout mice develop parenchymal iron overload: A putative role for class I genes of the major histocompatibility complex in iron metabolism.

  • B. RothenbergJ. Voland
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1996
Results indicate beta2m-associated proteins are involved in the control of intestinal Fe absorption, and predicted that mice which have altered expression of class I gene products, the beta2-microglobulin knockout mice, would develop Fe overload, were confirmed.

Isolation of CA dinucleotide repeats close to D6S105; linkage disequilibrium with haemochromatosis.

It is demonstrated by fluorescent in situ hybridisation that D6S105 lies at least 1-2 Mb telomeric of HLA-A, and a linkage disequilibrium study, with two of these microsatellites, in HC patients and controls lends support to the conclusion that D 6S105 is a close marker to the haemochromatosis gene.

Alleles at D6S265 and D6S105 define a haemochromatosis‐specific genotype

It is suggested that the haemochromatosis gene is located on the telomeric side of HLA‐A and define a possible haplotype in which the first mutation may have occurred.

Localization of the hemochromatosis gene close to D6S105.

P pedigree data indicate an association between HC and specific alleles at HLA-A and D6S105 allele 8, and a multipoint map indicates that the HC gene is located in a region less than 1 cM proximal to HLA -A and less than1 cM telomeric of HLA,A.

Hereditary hemochromatosis. Analysis of laboratory expression of the disease by genotype in 18 pedigrees.

Seven measures of iron metabolism evaluated by both chemical and histological methods showed a per cent saturation of transferrin above 62% to be the best simply-measured indicator of the affected genotype: homozygosity is accurately predicted in 92% of the cases.

Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis.

This finding strongly supports the suggestion that idiopathic haemochromatosis is a genetic disease and suggests that the gene(s) responsible for the disease may be linked to the histocompatibility genes.