Skip to main content
NCBI home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 1998 Nov;35(11):954–956. doi: 10.1136/jmg.35.11.954

Non-C282Y familial iron overload: evidence for locus heterogeneity in haemochromatosis.

S Pinson 1, J Yaouanq 1, A M Jouanolle 1, B Turlin 1, H Plauchu 1
PMCID: PMC1051492  PMID: 9832046

Abstract

Haemochromatosis (HC) is an autosomal recessive disease with progressive iron overload leading to midlife onset of clinical complications. The causal gene (HFE) maps to 6p, in close linkage with the HLA class I genes. An HFE candidate gene recently identified has two missense mutations (C282Y and H63D) associated with the disease. Here we document the phenotypic and genetic analysis of a nuclear family comprising two sibs with symptomatic and massive iron overload before the age of 25. The disease seemed to be recessively transmitted and fitted the agreed criteria for haemochromatosis, but was neither associated with the C282Y and H63D mutations nor linked with HLA markers. Our data strongly support locus heterogeneity in haemochromatosis by showing evidence that the gene responsible for juvenile haemochromatosis (JH) does not map to 6p. In the absence of clear cut phenotypic distinction from typical haemochromatosis, patients below 30 years of age and C282Y negative should be considered as putative juvenile cases. This has practical implications in genetic counselling and family management.

Full text

PDF
954

Selected References

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

  1. Ajioka R. S., Jorde L. B., Gruen J. R., Yu P., Dimitrova D., Barrow J., Radisky E., Edwards C. Q., Griffen L. M., Kushner J. P. Haplotype analysis of hemochromatosis: evaluation of different linkage-disequilibrium approaches and evolution of disease chromosomes. Am J Hum Genet. 1997 Jun;60(6):1439–1447. doi: 10.1086/515466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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. 1986 Jan-Feb;6(1):24–29. doi: 10.1002/hep.1840060106. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Borecki I. B., Rao D. C., Yaouanq J., Lalouel J. M. Serum ferritin as a marker of affection for genetic hemochromatosis. Hum Hered. 1990;40(3):159–166. doi: 10.1159/000153924. [DOI] [PubMed] [Google Scholar]
  5. Borot N., Roth M., Malfroy L., Demangel C., Vinel J. P., Pascal J. P., Coppin H. Mutations in the MHC class I-like candidate gene for hemochromatosis in French patients. Immunogenetics. 1997;45(5):320–324. doi: 10.1007/s002510050211. [DOI] [PubMed] [Google Scholar]
  6. Camaschella C., Roetto A., Cicilano M., Pasquero P., Bosio S., Gubetta L., Di Vito F., Girelli D., Totaro A., Carella M. Juvenile and adult hemochromatosis are distinct genetic disorders. Eur J Hum Genet. 1997 Nov-Dec;5(6):371–375. [PubMed] [Google Scholar]
  7. Carella M., D'Ambrosio L., Totaro A., Grifa A., Valentino M. A., Piperno A., Girelli D., Roetto A., Franco B., Gasparini P. Mutation analysis of the HLA-H gene in Italian hemochromatosis patients. Am J Hum Genet. 1997 Apr;60(4):828–832. [PMC free article] [PubMed] [Google Scholar]
  8. Deugnier Y. M., Loréal O., Turlin B., Guyader D., Jouanolle H., Moirand R., Jacquelinet C., Brissot P. Liver pathology in genetic hemochromatosis: a review of 135 homozygous cases and their bioclinical correlations. Gastroenterology. 1992 Jun;102(6):2050–2059. doi: 10.1016/0016-5085(92)90331-r. [DOI] [PubMed] [Google Scholar]
  9. Deugnier Y. M., Turlin B., Powell L. W., Summers K. M., Moirand R., Fletcher L., Loréal O., Brissot P., Halliday J. W. Differentiation between heterozygotes and homozygotes in genetic hemochromatosis by means of a histological hepatic iron index: a study of 192 cases. Hepatology. 1993 Jan;17(1):30–34. [PubMed] [Google Scholar]
  10. 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]
  11. Gandon G., Jouanolle A. M., Chauvel B., Mauvieux V., le Treut A., Feingold J., Le Gall J. Y., David V., Yaouanq J. Linkage disequilibrium and extended haplotypes in the HLA-A to D6S105 region: implications for mapping the hemochromatosis gene (HFE). Hum Genet. 1996 Jan;97(1):103–113. doi: 10.1007/BF00218843. [DOI] [PubMed] [Google Scholar]
  12. Jazwinska E. C., Cullen L. M., Busfield F., Pyper W. R., Webb S. I., Powell L. W., Morris C. P., Walsh T. P. Haemochromatosis and HLA-H. Nat Genet. 1996 Nov;14(3):249–251. doi: 10.1038/ng1196-249. [DOI] [PubMed] [Google Scholar]
  13. Jouanolle A. M., Gandon G., Jézéquel P., Blayau M., Campion M. L., Yaouanq J., Mosser J., Fergelot P., Chauvel B., Bouric P. Haemochromatosis and HLA-H. Nat Genet. 1996 Nov;14(3):251–252. doi: 10.1038/ng1196-251. [DOI] [PubMed] [Google Scholar]
  14. Lamon J. M., Marynick S. P., Roseblatt R., Donnelly S. Idiopathic hemochromatosis in a young female. A case study and review of the syndrome in young people. Gastroenterology. 1979 Jan;76(1):178–183. [PubMed] [Google Scholar]
  15. Powell L. W., Bassett M. L., Axelsen E., Ferluga J., Halliday J. W. Is all genetic (hereditary) hemochromatosis HLA-associated. Ann N Y Acad Sci. 1988;526:23–33. doi: 10.1111/j.1749-6632.1988.tb55489.x. [DOI] [PubMed] [Google Scholar]
  16. Rhodes D. A., Raha-Chowdhury R., Cox T. M., Trowsdale J. Homozygosity for the predominant Cys282Tyr mutation and absence of disease expression in hereditary haemochromatosis. J Med Genet. 1997 Sep;34(9):761–764. doi: 10.1136/jmg.34.9.761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Tay G. K., Leelayuwat C., Chorney M. J., Cattley S. K., Hollingsworth P. N., Witt C. S., Daly L. N., Hughes A., Dawkins R. L. The MHC contains multiple genes potentially relevant to hemochromatosis. Immunogenetics. 1997;45(5):336–340. [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES