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Blood, 1 April 2004, Vol. 103, No. 7, pp. 2835-2840.
Prepublished online as a Blood First Edition Paper on December 11, 2003; DOI 10.1182/blood-2003-10-3366.
Submitted October 1, 2003
Accepted December 9, 2003
HAMP AS A MODIFIER GENE THAT INCREASE THE PHENOTYPIC EXPRESSION OF THE HFE p.C282Y HOMOZYGOUS GENOTYPE
Sandrine JACOLOT, Gerald LE GAC, Virginie SCOTET, Isabelle QUERE, Catherine MURA, and Claude FEREC*
INSERM EMI 0115, Brest, France; Universite de Bretagne Occidental, Brest, France
INSERM EMI 0115, Brest, France; Etablissement Francais du Sang, Brest, France
INSERM EMI 0115, Brest, France
INSERM EMI 0115, Brest, France; Centre Hospitalier Universitaire, Brest, France
INSERM EMI 0115, Brest, France; Etablissement Francais du Sang, Brest, France; Centre Hospitalier Universitaire, Brest, France
* Corresponding author; email: claude.ferec{at}univ-brest.fr.
Hereditary hemochromatosis is a genetically heterogeneous disease of iron metabolism. The most common form of the disorder is a adult-onset form which has mainly been associated with the HFE p.C282Y/p.C282Y genotype. The phenotypic expression of this genotype is very heterogeneous and could be modulated by both environmental factors and modifier genes. The non-HFE hereditary hemochromatosis forms include a juvenile onset form associated with mutations in HAMP. From a cohort of 392 C282Y homozygous patients, we found 5 carriers of an additional HAMP mutation at the heterozygous state (p.R59G, p.G71D or p.R56X). We found that iron indices of these five patients were among the most elevated of the cohort. Moreover, we specified that the HAMP mutations were not detected in 300 control subjects. These results revealed that mutations in HAMP might increase the phenotypic expression of the p.C282Y/p.C282Y genotype. From a cohort of 31 patients with at least one chromosome lacking an HFE mutation, we further identified four males carrying a heterozygous HAMP mutation (p.59G or p.G71D). Based on a digenic model of inheritance, these data suggest that the association of heterozygous mutations in the HFE and HAMP genes could lead, at least in some cases, to an adult-onset form of primary iron overload.
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