Human Genetics

, Volume 97, Issue 4, pp 476–481 | Cite as

Allelic association of microsatellites of 6p in Italian hemochromatosis patients

  • C. Camaschella
  • A. Roetto
  • P. Gasparini
  • A. Piperno
  • P. Fortina
  • S. Surrey
  • E. Rappaport
Original Investigation


Hemochromatosis (HC) is an inherited disorder of iron metabolism and is frequently seen in Caucasians. The biochemical defect and the responsible gene are unknown, but the HC locus is closely linked to HLA-A on human chromosome 6 in the region 6p21.3. Although extensive studies have been performed in several populations, the precise location of the gene is still undefined. Linkage disequilibrium with HC has been detected for loci that are 3 cM apart: HLA class I and D6S105, which is located on the telomeric side of HLA-A. We have analyzed the inheritance of several multi-allele polymorphisms that map to 6p (D6S265, Y52, HLA-F, D6S306, D6S105, D6S464, D6S299) in 34 Italian HC families and in 17 unrelated patients. Significant association with HC was shown for alleles of multiple markers in the HLA-A region, for the distant marker D6S 105, but not for the D6S299 marker at 4 cM from HLA-A on the telomeric side. HC status was unambiguously assigned to 70 affected and 63 unaffected chromosomes from family studies. Thirty five different haplotypes were found in 70 HC chromosomes when considering four markers most tighly associated with the disease. A predominant haplotype comprising alleles 1-3-1-8 (marker order D6S265, HLA-A, Y52, D6S 105) accounted for 30% of the HC chromosomes and was absent in normals. A minority of other HC haplotypes could be related to the major haplotype by assuming single crossover events. Results of haplotype studies suggest a founder effect in the Italian population, as previously shown in Australian patients, and a possible common mutation shared with affected individuals of Celtic origin.


Hemochromatosis Crossover Event Allelic Association D6S299 Marker Major Haplotype 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abderrahim H, Sambucy JL, Iris F, Ougen P, Billault A, Chumakov IM, Dausset J, et al (1994) Cloning the human major histocompatibility complex in YACs. Genomics 23:520–527Google Scholar
  2. Applied Biosystems (1991) Synthesis of fluorescent dye-labeled oligonucleotides for use as primers in fluorescent-based DNA sequencing. ABI User Bulletin 11:6–9Google Scholar
  3. Bowcock AM, Tomfohrde J, Weissenbach J, Bonne-Tamir B, St George-Hyslop P, Giagheddu M, Cavalli Sforza LL (1994) Refining the position of Wilson disease by linkage disequilibrium with polymorphic microsatellites. Am J Hum Genet 54:79–87Google Scholar
  4. Camaschella C, Gasparini P (1994) Hunting the hemochromatosis gene: progress and problems. Eur J Hum Genet 2:141–147Google Scholar
  5. Camaschella C, Roetto A, De Sandre G, Pipemo A, Totaro A, Dianzani I, Gasparini P (1993) Construction of a genetic map telomeric to HLA-A by microsatellite analysis. Mol Cell Probes 7:411–414Google Scholar
  6. Campbell RD, Trowsdale J (1993) Map of the human MHC. Immunol Today 14:349–352Google Scholar
  7. Caruthers MH, Barone AD, Beaucage SL, Dodds DR, Fisher EF, McBride LJ, Matteucci M, et al (1987) Chemical synthesis of deoxyoligonucleotides by the phosphoramidite method. Methods Enzymol 154:287–313Google Scholar
  8. David V, Papadopoulos P, Yaouanq J, et al (1989) Ferritin H gene polymorphism in idiopathic hemochromatosis. Hum Genet 81: 123–126Google Scholar
  9. Dianzani I, Giannattasio S, De Sanctis L, Marra E, Ponzone A, Camaschella C, Piazza A (1994) Genetic history of phenylketonuria mutations in Italy. Am J Hum Genet 55: 851–853Google Scholar
  10. Draper DE, Gold L (1980) A method for linking fluorescent labels to polynucleotides: application to studies of ribosome-ribonucleic acid interaction. Biochemistry 19: 1774–1781Google Scholar
  11. Edwards CQ, Kushner JP (1993) Current concepts. Screening for hemochromatosis. N Engl J Med 328: 1616–1620Google Scholar
  12. El Kahloun A, Chauvet B, Mauvieux V, Dorval I, Jouanoll AM, Gicquel I, Le Gall JY, et al (1993) Localization of seven new genes around the HLA-A locus. Hum Mol Genet 2: 55–60Google Scholar
  13. Estivill X, Farral M, Williamson R, Ferrari M, Seia M, Giunta AM, Novelli G, et al (1988) Linkage disequilibrium between cystic fibrosis and linked DNA polymorphisms in Italian families: a collaborative study. Am J Hum Genet 43: 23–28Google Scholar
  14. Gasparini P, Borgato L, Pipemo A, Girelli D, Olivieri O, Gottardi E, Roetto A, et al (1993) Linkage analysis of 6p21 polymorphic markers and the hereditary hemochromatosis: localization of the gene centromeric to HLA-F. Hum Mol Genet 5: 571–576Google Scholar
  15. Goei VL, Parimoo S, Capossela A, Chu TW, Gruen JR (1994) Isolation of novel non-HLA-gene fragments from the hemochromatosis region (6p21.3) by cDNA hybridization selection. Am J Hum Genet 54: 244–251Google Scholar
  16. Gyapay G, Morisette J, Vignal A, Dib C, Fizames C, Millasseau P, Marc S, et al (1994) The 1993–1994 Genethon human genetic linkage map. Nature Genet 7: 246–339Google Scholar
  17. Jazwinska EC, Lee SC, Webb SI, Halliday JW, Powell LW (1993) Localization of the hemochromatosis gene close to D6S 105. Am J Hum Genet 53: 347–352Google Scholar
  18. Jazwinska EC, Pyper WR, Burt MJ, Francis JL, Goldwunn S, Webb SI, Lee SC, et al (1995) Haplotype analysis in Australian hemochromatosis patients: evidence for a predominant ancestral haplotype exclusively associated with hemochromatosis. Am J Hum Genet 56: 428–433Google Scholar
  19. Jorde LB (1995) Linkage disequilibrium as a gene-mapping tool. Am J Hum Genet 56: 11–14Google Scholar
  20. Kaplan NL, Hill WG, Weir BS (1995) Likelihood methods for locating disease genes in nonequilibrium populations. Am J Hum Genet 56: 18–32Google Scholar
  21. MacDonald ME, Lin C, Srinidhi L, Bates G, Altherr M, Whaley WL, Lehrach H, et al (1991) Complex patterns of linkage disequilibrium in the Huntington disease region. Am J Hum Genet 49:723–734Google Scholar
  22. MacDonald ME, Novelletto A, Lin C, Tagle D, Barnes G, Bats G, Taylor S (1992) The Huntington's disease candidate region exhibits many different haplotypes. Nature Genet 1: 99–103Google Scholar
  23. Ott J (1991) Analysis of human genetic linkage. Johns Hopkins University Press, BaltimoreGoogle Scholar
  24. Piazza A, Cappello N, Olivetti E, Rendine S (1988) A genetic history of Italy. Ann Hum Genet 52: 203–213Google Scholar
  25. Poncz M, Solowiejzcyk D, Harpel B, Mory Y, Schwartz E, Surrey S (1982) Construction of human gene libraries from small amounts of peripheral blood: analyses of β-like globin genes. Hemoglobin 6: 27–36Google Scholar
  26. Powell LW, Jazwinska E, Halliday JW (1994) Primary iron overload. In: Brock JH, Halliday JW, Pippard MJ, Powell LW (eds) Iron metabolism in health and disease. Saunders, London, pp 227–270Google Scholar
  27. Radisky ES, Ajioka RS, Edwards CQ, Griffen LM, Kushner JP (1994) Mapping recombinant events with molecular markers in hemochromatosis pedigrees. Cytogenet Cell Genet 67: 126–128Google Scholar
  28. Ramsay M, Williamson R, Estivill X, Wainwright BJ, Ho MF, Halford S, et al (1993) Haplotype analysis to determine the position of a mutation among closely linked DNA markers. Hum Mol Genet 2:1007–1014Google Scholar
  29. Reed PW, Davies JL, Copeman JB, Bennet ST, Palmer SM, Pritchard LE, Gough SCL, et al (1994) Chromosome specific microsatellite sets for fluorescent-based semiautomated genome mapping. Nature Genet 7: 390–395Google Scholar
  30. Simon M, Bourel M, Fauchet R, Genetet B (1976) Association of HLA A3 and HLA B14 antigens with idiopathic hemochromatosis. Gut 17: 332–334Google Scholar
  31. Simon M, Le Mignon L, Faucher R, et al (1987) A study of 609 haplotypes marking for the hemochromatosis gene: mapping the gene near the HLA-A locus and characters required to define a heterozygous population; hypothesis concerning hemochromatosis HLA association. Am J Hum Genet 41: 89–124Google Scholar
  32. Stone C, Pointon JJ, Jazwinska EC, Halliday JW, Powell LW, Robson JH, Monaco AP, et al (1994) Isolation of CA dinucleotide repeats close to D6S105; linkage disequilibrium with haemochromatosis. Hum Mol Genet 3: 2043–2046Google Scholar
  33. Totaro A, Grifa A, Roetto A, Zelante L, Camaschella C, Gasparini P (1994) A new complex polymorphic repeat close to the HLA-A and HLA-E loci. Hum Genet 94: 578Google Scholar
  34. Totaro A, Grifa A, Roetto A, Lunardi C, D'Agruma L, Sbaiz L, Zelante L, et al (1995) New polymorphisms and markers in the HLA class I region: relevance to the hereditary hemochromatosis. Hum Genet 95: 429–434Google Scholar
  35. Volz A, Boyle JM, Cann HM, Cottingham RW, Orr HT, Ziegler A (1994) Report of the Second International Workshop on Human Chromosome 6. Genomics 21: 464–472Google Scholar
  36. Weber JL, Kwitek AE, May PE, Zoghbi HY (1991) Dinucleotide repeat polymorphism at the D6S 105 locus. Nucleic Acids Res 19: 968Google Scholar
  37. Wei H, Fan WF, Xu H, Parimoo S, Shukla H, Chaplin DD, Weissman SM (1993) Genes in one megabase of the HLA class I region. Proc Natl Acad Sci USA 90: 11870–11874Google Scholar
  38. Worwood M, Raha-Chowdhury R, Dorak MT, Bowen DJ, Burnett AK (1994) Alleles at D6S265 and D6S105 define a haemochromatosis specific genotype. Br J Haematol 86: 863–866Google Scholar
  39. Worwood M, Gasparini P, Camaschella C (1995) Report on the International Workshop on Molecular Genetics of Hemochromatosis. J Med Genet 32: 320–323Google Scholar
  40. Yaouanq J, Perichon M, Chorney M, Pontarotti P, Le Treut A, El Kahloun A, Mauvieux V, et al (1994) Anonymous marker loci within 400 Kb of HLA-A generate haplotypes in linkage disequilibrium with the hemochromatosis gene (HFE). Am J Hum Genet 54: 252–263Google Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • C. Camaschella
    • 1
    • 2
  • A. Roetto
    • 1
  • P. Gasparini
    • 3
  • A. Piperno
    • 4
  • P. Fortina
    • 5
  • S. Surrey
    • 5
  • E. Rappaport
    • 5
  1. 1.Dipartimento di Scienze Biomediche e Oncologia UmanaUniversity di TorinoOrbassano TorinoItaly
  2. 2.CNR CIOS TorinoTorinoItaly
  3. 3.IRCCS CSSSan Giovanni RotondoItaly
  4. 4.Istituto di Scienze BiomedicheMilanItaly
  5. 5.Department of Pediatrics, The Children's Hospital of Philadelphia, University of PennsylvaniaSchool of MedicinePhiladelphiaUSA

Personalised recommendations