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

Abstract

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. Within this region, we have identified a gene related to the MHC class I family, termed HLA–H, containing two missense alterations. One of these is predicted to inactivate this class of proteins and was found homozygous in 83% of 178 patients. A role of this gene in haemochromatosis is supported by the frequency and nature of the major mutation and prior studies implicating MHC class Mike proteins in iron metabolism.

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References

  1. Dadone, M.M., Kushner, J.P., Edwards, C.Q., Bishop, D.T. & Skolnick, M.H. Hereditary hemochromatosis: analysis of laboratory expression of the disease by genotype in 18 pedigrees. Am. J. Clin. Pathol. 78, 196–207 (1982).

    Article  CAS  PubMed  Google Scholar 

  2. Edwards, C.Q. et al. Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N. Engl. J. Med. 318, 1355–1362 (1988).

    Article  CAS  PubMed  Google Scholar 

  3. McKusick, V.A. Mendelian inheritance in man (The Johns Hopkins University Press, Baltimore, 1994).

    Google Scholar 

  4. Bothwell, T.H., Charlton, R.W. & Motulski, A.G. in The metabolic and molecular bases of inherited disease (eds. Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D.) 2237–2269 (McGraw-Hill, New York, 1995).

    Google Scholar 

  5. Bacon, B.R. & Tavill, A.S., in Hepatology. A textbook of liver disease (eds. Zakim, D. & Boyer, T.D.) 1439–1472 (W.B. Saunders, Philadelphia, 1996).

    Google Scholar 

  6. Bomford, A. & Williams, R. Long-term results of venesection therapy in idiopathic haemochromatosis. Quart. J. Med. 45, 611–623 (1976).

    CAS  PubMed  Google Scholar 

  7. Milder, M.S., Cook, J.D., Stray, S. & Finch, C.A. Idiopathic hemochromatosis, an interim report. Medicine 59, 34–49 (1980).

    Article  CAS  PubMed  Google Scholar 

  8. Simon, M., Bourel, M., Fauchet, R. & Genetet, B. Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis. Gut 17, 332–334 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jazwinska, E.C., Lee, S.C., Webb, S.I., Halliday, J.W. & Powell, L.W. Localization of the hemochromatosis gene close to D6S105. Am. J. Hum. Genet. 53, 347–352 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Lalouel, J.M. et al. Genetic analysis of idiopathic hemochromatosis using both qualitative (disease status) and quantitative (serum iron) information. Am. J. Hum. Genet. 37, 700–718 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Boretto, J. et al. Anonymous markers located on chromosome 6 in the HLA-A class I region: allelic distribution in genetic haemochromatosis. Hum. Genet. 89, 33–36 (1992).

    Article  CAS  PubMed  Google Scholar 

  12. Yaouanq, J. et al. Anonymous marker loci within 400 kb of HLA-A generate haplotypes in linkage disequilibrium with the hemochromatosis gene (HFE). Am. J. Hum. Genet. 54, 252–263 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Totaro, A. et al. New polymorphisms and markers in the HLA class I region: relevance to hereditary hemochromatosis (HFE). Hum. Genet. 95, 429–434 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Edwards, C.Q., Griffen, L.M., Dadone, M.M., Skolnick, M.H. & Kushner, J.P. Mapping the locus for hereditary hemochromatosis: localization between HLA-B and HLA-A. Am. J. Hum. Genet. 38, 805–811 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Gasparini, P. et al. Linkage analysis of 6p21 polymorphic markers and the hereditary hemochromatosis: localization of the gene centromeric to HLA-F. Hum. Mol. Genet. 2, 571–576 (1993).

    Article  CAS  PubMed  Google Scholar 

  16. Powell, L.W. et al. Expression of hemochromatosis in homozygous subjects. Gastroenterology. 98, 1625–1632 (1990).

    Article  CAS  PubMed  Google Scholar 

  17. Calandro, L.M., Baer, D.M. & Sensabaugh, G.F. Characterization of a recombinant that locates the hereditary hemochromatosis gene telomeric to HLA-F. Hum. Genet. 96, 339–342 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Jazwinska, E.C. et al. Haplotype analysis in australian hemochromatosis patients: evidence for a predominant ancestral haplotype exclusively associated with hemochromatosis. Am. J. Hum. Genet. 56, 428–433 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Raha-Chowdhury, R. et al. New polymorphic microsatellite markers place the haemochromatosis gene telomeric to D6S105. Hum. Mol. Genet. 4, 1869–1874 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Stone, C. Isolation of CA dinucleotide repeats close to D6S105; linkage disequilibrium with haemochromatosis. Hum. Mol. Genet. 3, 2043–2046 (1994).

    CAS  PubMed  Google Scholar 

  21. Seese, N.K. et al. Localization of the hemochromatosis gene: linkage disequilibrium analysis using an American patient collection. Blood Cells Mol. Dis. 22, 36–46 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Worwood, M. et al. Alleles at D6S265 and D6S105 define a haemochromatosis-specific genotype. Brit. J. Haematol. 86, 863–866 (1994).

    Article  CAS  Google Scholar 

  23. Gandon, G. . et al. Linkage disequilibrium and extended haplotypes in the HLA-A to D6S105 region: implications for mapping the hemochromatosis gene (HFE). Hum. Genet. 97, 103–113 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Cohen, D., Chumakov, I. & Weissenbach, J. A first-generation physical map of the human genome. Nature 366, 698–701 (1993).

    Article  CAS  PubMed  Google Scholar 

  25. Chumakov, I.M. et al. A YAC contig map of the human genome. Nature 377 Suppl., 175–183 (1995).

    CAS  PubMed  Google Scholar 

  26. Hudson, T. et al. An STS-based map of the human genome. Science 270, 1945–1954 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Ferrin, L.J. & Camerini-Otero, R.D. Selective cleavage of human DNA: recA-assisted restriction endonuclease (RARE) cleavage. Science 254, 1494–1497 (1991).

    Article  CAS  PubMed  Google Scholar 

  28. Gnirke, A., ladonato, S.P., Kwok, P.-Y., & Olson, M.V., Physical calibration of yeast artificial chromosome contig maps by recA-assisted restriction endonuclase (RARE) cleavage. Genomics 24, 199–210 (1994).

    Article  CAS  PubMed  Google Scholar 

  29. Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152–154 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Kerem, B.-T. et al. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073–1080 (1989).

    Article  CAS  PubMed  Google Scholar 

  31. Hästbacka, J. et al. The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell 78, 1073–1087 (1994).

    Article  PubMed  Google Scholar 

  32. Lehesjoki, A.-E. et al. Localization of the EPM1 gene for progressive myoclonus epilepsy on chromosome 21: linkage disequilibrium allows high resolution mapping. Hum. Mol. Genet. 2, 1229–1234 (1993).

    Article  CAS  PubMed  Google Scholar 

  33. Bengtsson, B.O. & Thomson, G. Measuring the strength of associations between HLA antigens and diseases. Tissue Antigens 18, 356–363 (1981).

    Article  CAS  PubMed  Google Scholar 

  34. Lovett, M., Kere, J. & Hinton, L.M. Direct selection: a method for the isolation of cDNAs encoded by large genomic regions. Proc. Natl. Acad. Sci. USA 88, 9628–9632 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Church, D.M. et al. Isolation of genes from complex sources of mammalian genomic DNA using exon amplification. Nature Genet. 6, 98–105 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. Itoh, K., Itoh, Y. & Frank, M.B. Protein heterogeneity in the human Ro/SSA ribonucleoproteins: the 52- and 60-kD Ro/SSA autoantigens are encoded by separate genes. J. Clin. Invest. 87, 177–186 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chong, S.S., Kristjansson, K., Zoghbi, H.Y. & Hughes, M.R. Molecular cloning of the cDNA encoding a human renal sodium phosphate transport protein and its assignment to chromosome 6p21. 3-p23. Genomics 18, 355–359 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. Selavakumar, A. et al. A novel subtype of A2 (A*0217) isolated from the South American Indian B-cell line AMALA. Tissue Ant. 45, 343–347 (1995).

    Article  Google Scholar 

  39. Orr, H.T. Lopez de Castro, J.A., Parham, R., Ploegh, H.L., & Strominger, J.L. Comparison of amino acid sequences of two human histocompatibility antigens, HLA-A2 and HLA-B7: location of putative alloantigenic sites. Proc. Natl.Acad.Sci. USA 76, 4395–4399 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hood, L., Kronenberg, M. & Hunkapiller, T. T cell antigen receptors and the immunoglobulin supergene family. Cell 40, 225–229 (1985).

    Article  CAS  PubMed  Google Scholar 

  41. Stroynowski, I. Molecules related to class-l major histocompatibility complex antigens. Ann. Rev. Immunol. 8, 501–530 (1990).

    Article  CAS  Google Scholar 

  42. Simister, N.E. & Mostov, K.E., An Fc receptor structurally related to MHC class I antigens. Nature 337, 184–187 (1989).

    Article  CAS  PubMed  Google Scholar 

  43. Bjorkman, P.J. & Parham, P., Structure, function, and diversity of class I major histocompatibility complex molecules. Ann. Rev. Biochem. 59, 253–288 (1990).

    Article  CAS  PubMed  Google Scholar 

  44. Miyazaki, J., Apella, E. & Ozato, K. Intracellular transport blockade caused by disruption of the disulfide bridge in the third external domain of major histocompatibility complex class I antigen. Proc. Natl. Acad. Sci. USA 83, 757–761 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Madden, D.R., Gorga, J.C., Strominger, J.L. & Wiley, D.C. The three-dimensional structure of HLA-B27 at 2.1 Å resolution suggests a general mechanism for tight peptide binding to MHC. Cell 70, 1035–1048 (1992).

    Article  CAS  PubMed  Google Scholar 

  46. Burmeister, W.P., Gastinel, L.N., Simister, N.E., Blum, M.L. & Bjorkman, P.J. Crystal structure at 2.2 Å resolution of the MHC-related neonatal Fc receptor. Nature 372, 336–343 (1994).

    Article  CAS  PubMed  Google Scholar 

  47. Burt, M.J., Smit, D.J., Pyper, W.R., Powell, L.W. & Jazwinska, E.C. A 4.5-Megabase YAC contig and physical map over the haemochromatosis gene region. Genomics 33, 153–158 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Hudson, T. et al. An STS-based map of the human genome. Science 270, 1945–1954, with supplementary data from the Whitehead Institute/MIT Center for Genome Research, human genetic mapping project, data release 10(May 1996) (1995).

    Article  CAS  PubMed  Google Scholar 

  49. Bjorkman, P.J. et al. Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329, 506–512 (1987).

    Article  CAS  PubMed  Google Scholar 

  50. De Sousa, M. et al. Iron overload in β2-microglobulin-deficient mice. Immunol. Lett. 39, 105–111 (1994).

    Article  CAS  PubMed  Google Scholar 

  51. Rothenberg, B.E. & Voland, J.R. β2 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. USA 93, 1529–1534 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zijlstra, M. et al. β2-microglobulin deficient mice lack CD4−8+ cytolytic T cells. Nature 344, 742–746 (1990).

    Article  CAS  PubMed  Google Scholar 

  53. Koller, B.H., Marrack, P., Kappler, J.W. & Smithies, 0 . Normal development of mice deficient in β2M, MHC class I proteins, and CD8+ T cells. Science 248, 1227–1230 (1990).

    Article  CAS  PubMed  Google Scholar 

  54. RauletD, H. MHC class l-deficient mice. Adv. Immun. 55, 381–421 (1994).

    Article  Google Scholar 

  55. Arosa, F.A. et al. Decreased CD8-p56lck activity in peripheral blood T-lymphocytes from patients with hereditary hemochromatosis. Scand. J. Immunol. 39, 426–432 (1994).

    Article  CAS  PubMed  Google Scholar 

  56. Story, C.M., Mikulska, J. & Simister, N.E. A major histocompatibility complex classl-like Fc receptor cloned from human placenta. J. Exp. Med. 180, 2377–2381 (1994).

    Article  CAS  PubMed  Google Scholar 

  57. Ueyama, H., Deng, H.X. & Ohkubo, I. Molecular cloning and chromosomal assignment of the gene for human Zn-α2-glycoprotein. Biochemistry. 32, 12968–12976 (1993).

    Article  CAS  PubMed  Google Scholar 

  58. McLaren, G.D., Nathanson, M.H., Jacobs, A., Trevett, D. & Thomson, W. Regulation of intestinal iron absorption and mucosal iron kinetics in hereditary hemochromatosis. J. Lab. Clin. Med. 117, 390–401 (1991).

    CAS  PubMed  Google Scholar 

  59. Schreiber, A.B., Schlessinger, J. & Edidin, M. Interaction between major histocompatibility complex antigens and epidermal growth factor receptors on human cells. J. Cell Biol. 98, 725–731 (1984).

    Article  CAS  PubMed  Google Scholar 

  60. Veriand, S. et al. Specific molecular interaction between the insulin receptor and a D product of MHC class 1. J. Immun. 143, 945–951 (1989).

    Google Scholar 

  61. Crawford, D.H.G. et al. Evidence that the ancestral haplotype in Australian hemochromatosis patients may be associated with a common mutation in the gena. Am. J. Hum. Genet. 57, 362–367 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Bassett, M.L., Halliday, J.W. & Powell, L.W. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology 6, 24–29 (1986).

    Article  CAS  PubMed  Google Scholar 

  63. Wolff, R.K. et al. Analysis of chromosome 22 deletions in neurofibromatosis type 2-related tumors. Am. J. Hum. Genet. 51, 478–485 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Jackson, C.L., in Current protocols in human genetics (eds Dracopoli, N. C. et al.) (J. Wiley and Sons, New York, 1994).

    Google Scholar 

  65. Riley, J. et al. A novel, rapid method for the isolation of terminal sequences from yeast artificial chromosome (YAC) clones. Nucl. Acids Res. 18, 2887–2890 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Shizuya, H. et al. Cloning and stable maintenance of 300-kilobase-pair fragments of human DNA in Escherichia coli using an F-factor-based vector. Proc. Natl. Acad. Sci. USA 89, 8794–8797 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. loannou, P.A. et al. A new bacteriophage P1-derived vector for the propagation of large human DMA fragments. Nature Genet. 6, 84–89 (1994).

    Article  Google Scholar 

  68. Shepherd, N.S. et al. Preparation and screening of an arrayed human genomic library generated with the P1 cloning system. Proc. Natl. Acad. Sci. USA 91, 2629–2633 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hudson, T.J., in Current protocols in human genetics (eds Dracopoli, N. C. et al.) (J. Wiley and Sons, New York, 1994).

    Google Scholar 

  70. Fullan, A. & Thomas, W. A polymorphic dinucleotide repeat at the human HLA-F locus. Hum. Mol. Genet. 3, 2266 (1994).

    Article  CAS  PubMed  Google Scholar 

  71. Weber, J.L. & May, R.E. Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am. J. Hum. Genet. 44, 388–396 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Morgan, J.G., polganov, G.M., Robbins, S.E., Hinton, L.M., & Lovett, M. The selective isolation of novel cDNAs encoded by the regions surrounding the human interleukin 4 and 5 genes. Nucl. Acids Res. 20, 5173–5179 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Delahunty, C., Ankener, W., Deng, Q., Eng, J. & Nickerson, D.A. Testing the feasibility of DNA typing for human identification by PCR and an oligonucleotide ligation assay. Am. J. Hum. Genet. 58, 1239–1246 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Strathmann, M. et al. Transposon-facilitated DNA sequencing. Proc. Natl. Acad. Sd. USA 88, 1247–1250 (1991).

    Article  CAS  Google Scholar 

  75. Chen, E.Y., Schlessinger, D. & Kere, J. Ordered shotgun sequencing, a strategy for integrated mapping and sequencing of YAC clones. Genomics 17, 651–356 (1993).

    Article  CAS  PubMed  Google Scholar 

  76. Roach, J.C., Boysen, C., Wang, K. & Hood, L. Pairwise end sequencing: a unified approach to genomic mapping and sequencing. Genomics 26, 345–353 (1995).

    Article  CAS  PubMed  Google Scholar 

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Feder, J., Gnirke, A., Thomas, W. et al. A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13, 399–408 (1996). https://doi.org/10.1038/ng0896-399

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