Skip to main content
NCBI home page
Molecular Medicine logoLink to Molecular Medicine
. 1997 Jun;3(6):397–402.

HLA-H and associated proteins in patients with hemochromatosis.

E Beutler 1, C West 1, T Gelbart 1
PMCID: PMC2230203  PMID: 9234244

Abstract

BACKGROUND: The 845A(C282Y) mutation in the HLA-H gene accounts for most cases of hereditary hemochromatosis in patients who are of European origin. Some lack this mutation, however, and it is not present in Asian patients. Thus, other mutations either in HLA-H or associated proteins may be present in such patients. HLA-H associates with beta-2-microglobulin. Calreticulin associates with class 1 HLA proteins and appears to be identical with mobilferrin, a putative iron transport protein. These two proteins are therefore candidates for mutations in patients with hemochromatosis. MATERIALS AND METHODS: We have sequenced the coding region and parts of introns of the HLA-H gene, the beta-2-microglobulin gene, and the calreticulin (mobilferrin) gene of 10, 7, and 5 hemochromatosis patients, respectively, selecting those who were not homozygous for the 845A(C282Y) mutation. The number of chromosomes at risk studied were 18 for HLA-H, 14 for beta-2-microglobulin and 10 for calreticulin. RESULTS: We detected 3 new intronic polymorphisms in the HLA-H gene, each a point mutation. Some differences from published sequences of beta-2-microglobulin and calreticulin were documented, but these were uniformly present in all samples. CONCLUSIONS: The lack of additional mutations in the HLA-H gene is remarkable, and we speculate that the C282Y mutation may be a gain-of-function change.

Full text

PDF
397

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Beutler E., Gelbart T., West C., Lee P., Adams M., Blackstone R., Pockros P., Kosty M., Venditti C. P., Phatak P. D. Mutation analysis in hereditary hemochromatosis. Blood Cells Mol Dis. 1996;22(2):187–194b. doi: 10.1006/bcmd.1996.0027. [DOI] [PubMed] [Google Scholar]
  2. Bulaj Z. J., Griffen L. M., Jorde L. B., Edwards C. Q., Kushner J. P. Clinical and biochemical abnormalities in people heterozygous for hemochromatosis. N Engl J Med. 1996 Dec 12;335(24):1799–1805. doi: 10.1056/NEJM199612123352403. [DOI] [PubMed] [Google Scholar]
  3. Conrad M. E., Umbreit J. N., Moore E. G. Rat duodenal iron-binding protein mobilferrin is a homologue of calreticulin. Gastroenterology. 1993 Jun;104(6):1700–1704. doi: 10.1016/0016-5085(93)90648-v. [DOI] [PubMed] [Google Scholar]
  4. Feder J. N., Gnirke A., Thomas W., Tsuchihashi Z., Ruddy D. A., Basava A., Dormishian F., Domingo R., Jr, Ellis M. C., Fullan A. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996 Aug;13(4):399–408. doi: 10.1038/ng0896-399. [DOI] [PubMed] [Google Scholar]
  5. Mahuran D. J. Beta-hexosaminidase: biosynthesis and processing of the normal enzyme, and identification of mutations causing Jewish Tay-Sachs disease. Clin Biochem. 1995 Apr;28(2):101–106. doi: 10.1016/0009-9120(95)00003-r. [DOI] [PubMed] [Google Scholar]
  6. Powell L. W., Jazwinska E. C. Hemochromatosis in heterozygotes. N Engl J Med. 1996 Dec 12;335(24):1837–1839. doi: 10.1056/NEJM199612123352410. [DOI] [PubMed] [Google Scholar]
  7. Rothenberg B. E., Voland J. R. beta2 knockout mice develop parenchymal iron overload: A putative role for class I genes of the major histocompatibility complex in iron metabolism. Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1529–1534. doi: 10.1073/pnas.93.4.1529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Sadasivan B., Lehner P. J., Ortmann B., Spies T., Cresswell P. Roles for calreticulin and a novel glycoprotein, tapasin, in the interaction of MHC class I molecules with TAP. Immunity. 1996 Aug;5(2):103–114. doi: 10.1016/s1074-7613(00)80487-2. [DOI] [PubMed] [Google Scholar]
  9. Santos M., Schilham M. W., Rademakers L. H., Marx J. J., de Sousa M., Clevers H. Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man. J Exp Med. 1996 Nov 1;184(5):1975–1985. doi: 10.1084/jem.184.5.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Sferra T. J., Collins F. S. The molecular biology of cystic fibrosis. Annu Rev Med. 1993;44:133–144. doi: 10.1146/annurev.me.44.020193.001025. [DOI] [PubMed] [Google Scholar]
  11. Shore S., Tomczak J., Grebner E. E., Myerowitz R. An unusual genotype in an Ashkenazi Jewish patient with Tay-Sachs disease. Hum Mutat. 1992;1(6):486–490. doi: 10.1002/humu.1380010606. [DOI] [PubMed] [Google Scholar]
  12. Simon M., Pawlotsky Y., Bourel M., Fauchet R., Genetet B. Hémochromatose idiopathique Maladie associée à l'antigène tissulaire HL-A 3. Nouv Presse Med. 1975 May 10;4(19):1432–1432. [PubMed] [Google Scholar]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ

RESOURCES