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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.
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RED CELLS
HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype
Sandrine Jacolot,
Gerald Le Gac,
Virginie Scotet,
Isabelle Quere,
Catherine Mura, and
Claude Ferec
From Institut National de la Santé Et de la Recherche Médicale (INSERM) Equipe Mixte INSERM Université (EMIU) 0115, Brest, France; Etablissement Français du Sang, Brest, France; Centre Hospitalier Universitaire, Brest, France; and Université de Bretagne occidentale, Brest, France.
Hereditary hemochromatosis is a genetically heterogeneous disease of iron metabolism. The most common form of the disorder is an adult-onset form that has mainly been associated with the HFE pC282Y/pC282Y 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 (pR59G, pG71D, or pR56X). We found that iron indices of these 5 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 pC282Y/pC282Y genotype. From a cohort of 31 patients with at least one chromosome lacking an HFE mutation, we further identified 4 males carrying a heterozygous HAMP mutation (pR59G or pG71D). 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. (Blood. 2004;103:2835-2840)
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