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. 1997 Sep;34(9):761–764. doi: 10.1136/jmg.34.9.761

Homozygosity for the predominant Cys282Tyr mutation and absence of disease expression in hereditary haemochromatosis.

D A Rhodes 1, R Raha-Chowdhury 1, T M Cox 1, J Trowsdale 1
PMCID: PMC1051063  PMID: 9321765

Abstract

A candidate gene for hereditary haemochromatosis, HLA-H, has recently been presented. Two missense mutations in the HLA-H gene sequence are predicted to account for nearly 90% of all cases of the disease. The aim of this study was to correlate the presence of these missense mutations with the expressivity of the disease, as assessed by standard biochemical evaluation of serum iron parameters. Detection of the known mutations in haemochromatosis, Cys282Tyr and His63Asp, was undertaken in a large pedigree showing variable expression of the disease in successive generations. In three sibs with overt disease (one male, two female, aged 50 to 53 years), homozygosity for the predominant G to A transition (Cys282Tyr) in HLA-H was detected. However, homozygosity for this mutation was also detected in an asymptomatic male sib, aged 50, harbouring an identical genotype. The finding of an asymptomatic homozygous Cys282Tyr subject, haplo-identical to affected sibs, indicates that clinical expression of symptomatic disease is variable, even in middle aged Cys282Tyr homozygotes. This has profound implications for the future use of genetic screening for haemochromatosis.

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Selected References

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