Summary
The unknown allele that predisposes to the development of haemochromatosis in man has been localized to the HLA class I region on the short arm of chromosome 6. We have utilized pulsed-field gel electrophoresis in conjunction with probes that map within, or in the vicinity of, this region to search for structural lesions that may further define the disease locus. Using the enzyme Mlu I, fragments that associated specifically with the HLA-A23, A31 and B8 alleles were identified. However, in members of three pedigrees affected by haemochromatosis, and in six unrelated patients with the disorder, no disease-specific differences were detected in the DNA fragments with four restriction enzymes and eight probes when compared with healthy individuals. These data suggest that the lesion responsible for hereditary haemochromatosis lies beyond the resolution of this technique and does not involve large structural deletions or extensive re-arrangements in this highly polymorphic region of the genome.
Similar content being viewed by others
References
Anand R (1986) Pulsed field gel electrophoresis: a technique for fractioning large DNA molecules. Trends Genet 2:278–283
Bassett ML, Doran TJ, Halliday TW, Bashir HV, Powell LW (1982) Idiopathic haemochromatosis: demonstration of homozygous-heterozygous mating by HLA typing of families. Hum Genet 60:352–356
Bothwell TH, Charlton RW, Motulsky AG (1989) Hemochromatosis. In: Scriver CR, Beaudet AC, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6 edn. McGraw-Hill, New York, pp 1433–1462
Boyd D, Vecoli C, Belcher DM, Jain SK, Drysdale JW (1985) Structural and functional relationship of human ferritin H and L chains deduced from cDNA clones. J Biol Chem 260:11755–11761
Carroll MC, Katzman P, Alicot EM, Koller BH, Geraghty DE, Orr HT, Strominger JL, Spies T (1987) Linkage map of the human major histocompatibility complex including the tumor necrosis factor genes. Proc Natl Acad Sci USA 64:8535–8539
Chimini G, Pontarotti P, Nguyen C, Toubert A, Boretto J, Jordan BR (1988) The chromosome region containing the highly polymorphic HLA class I genes displays limited large scale variability in the human population. EMBO J 7:395–400
Cox TM, Lord DK (1989) Hereditary haemochromatosis. Eur J Haematol 42:113–125
Cragg SJ, Drysdale J, Worwood M (1985) Genes for the ‘H’ subunit of human ferritin are present on a number of human chromosomes. Hum Genet 71:108–112
Cuypers HT, Selten G, Berns A, Geurts van Kessel AHM (1986) Assignment of the human homologue of Pim-1, a mouse gene implicated in leukemogenesis, to the pter-q12 region of chromosome 6. Hum Genet 72:262–265
Domen J, Lindern M von, Hermans A, Breuer M, Grosveld G, Berns A (1987) Comparison of the human and mouse PIM-1 cDNAs: nucleotide sequence and immunological identification of the in vitro synthesised PIM-1 protein. Oncogene Res 1:103–112
Dunham I, Sargent CA, Trowsdale J, Campbell RD (1987) Molecular mapping of the human major histocompatibility complex by pulsed-field electrophoresis. Proc Natl Acad Sci USA 84:7237–7241
Dunham I, Sargent CA, Dawlens RL, Campbell RD (1989) An analysis of variation in the long-range genomic organization of the human major histocompatibility complex class II region by pulsed-field gel electrophoresis Genomics 5:787–796
Edwards CQ, Griffen LM, Goldgar D, Drummond C, Skolnick MH, Kushner JP (1988) Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med 318:1355–1362
Feinberg AP, Vogelstein B (1983) A technique for radio-labelling DNA restriction endonuclease fragments to a high specific activity. Anal Biochem 132:6–13
Kenwrick S, Patterson M, Speer A, Fischbeck K, Davies K (1987) Molecular analysis of the Duchenne muscular dystrophy region using pulsed field gel electrophoresis. Cell 48:351–357
Koller BH, Sidwell B, DeMars R, Orr HT (1984) Isolation of HLA locus-specific DNA probes from the 3′ -untranslated region. Proc Natl Acad Sci USA 81:5175–5178
Koller BH, Geraghty DE, Shimizu Y, DeMars R, Orr HT (1988) HLA-E: a novel HLA class I gene expressed in resting T lymphocytes. J Immunol 141:897–904
Lawrance SK, Smith CL, Srivastava R, Cantor CR, Weissman SM (1987) Megabase-scale mapping of the HLA gene complex by pulsed field gel electrophoresis. Science 235:1387–1390
Maniatis T, Frisch EF, Sambrook J (eds) (1982) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Nguyen C, Sodoyer R, Trucy J, Strachan T, Jordon BR (1985) The HLA-AW24 gene: sequence, surroundings and comparison with the HLA-A2 and HLA-A3 genes. Immunogenetics 21:479–489
Ommen GJB van, Verkerk JMH (1986) Restriction analysis of chromosomal DNA in a size range up to two million base pairs by pulsed field gradient electrophoresis. In: Davies KE (ed) Human genetic disease, a practical approach. IRL Press, Oxford, pp 113–133
Ragoussis R, Bloemer K, Pohla H, Messer G, Weiss EH, Ziegler A (1989) A physical map including a new class I gene (cda 12) of the human major histocompatibility complex (A2/B13 haplotype) derived from a monosomy mutant cell line. Genomics 4:301–308
Scheuer PJ, Williams R, Muir AR (1962) Hepatic pathology in relatives of patients with haemochromatosis. J Pathol Bacteriol 84:53–64
Shirai T, Yamaguchi H, Ito H, Todd CW, Wallace B (1985) Cloning and expression in Escherichia coli of the gene for human tumor necrosis factor. Nature 313:803–806
Simon M, Pawlotsky Y, Bourel M, Fauchet R, Genetet B (1975) Hemochromatose idiopathique: maladie associee a l'antigene tissulaire HLA-A3? Nouv Presse Med 4:1432
Simon M, Bourel M, Genetet B, Fauchet R (1977) Idiopathic hemochromatosis: demonstration of recessive transmission and early detection by family HLA typing. N Engl J Med 297:1017–1021
Simon M, Le Mignon L, Fauchet R, Yaouanq J, David V, Eden G, Bourel M (1987) A study of 609 HLA haplotypes marking for the hemochromatosis gene: (1) Mapping of the gene near the HLA-A locus and characters required to define a heterozygous population and (2) Hypothesis concerning the underlying cause of hemochromatosis-HLA association. Am J Hum Genet 41:89–105
Southern EM (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 98:503–517
Srivastava R, Chorney MJ, Lawrance SK, Pan J, Smith Z, Smith CL, Weissman SM (1987) Structure, expression and molecular mapping of a divergent member of the class I HLA gene family. Proc Natl Acad Sci USA 84:4224–4228
Strachan T, Dodge AB, Smillie D, Dyer PA, Sodoyer R, Jordon BR, Harris R (1986) An HLA-C specific DNA probe. Immunogenetics 23:115–120
Terasaki PI, Bernoco D, Park MS, Oztur KG, Iwaki Y (1978) Microdroplet testing for HLA-A, B, C, and D. Am J Clin Pathol 69:103–120
Tokunaga K, Saueracker G, Kay PH, Christiansen FT, Anand R, Dawkins RL (1988) Extensive deletions and insertions in different MHC supratypes detected by pulsed field gel electrophoresis. J Exp Med 168:933–940
Trowsdale J, Lee J, Kelly A, Carey J, Jenkins J, Travers P, Bodmer WF (1984) Isolation and sequencing of a cDNA clone for a human HLA-ABC antigen. Mol Biol Med 2:53–61
Weisberg LG, Shiu DT, Greenberg CS, Kan YW, Shuman MA (1987) Localization of the gene for coagulation factor XIIIa chain to chromosome 6 and identification of sites of synthesis. J Clin Invest 79:649–652
Wong P, Komarnicki L, Schoeder ML, Lewis M, Kaita H, Philipps S, Stranc L, McAlpine PJ (1988) Analysis for linkage between F13A and three chromosome 6 marker loci: evidence for 6pter: F13A:HLA:GLO1:CEN gene order. Hum Genet 79:228–230
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lord, D.K., Dunham, I., Campbell, R.D. et al. Molecular analysis of the human MHC class I region in hereditary haemochromatosis. Hum Genet 85, 531–536 (1990). https://doi.org/10.1007/BF00194232
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00194232