The C282Y mutation causing hereditary hemochromatosis does not produce a null allele

Targeted mutagenesis was used to produce two mutations in the murine hemoch romatosis gene (Hfe) locus. The first mutation deletes a large portion of t he coding sequence, generating a null allele. The second mutation introduce s a missense mutation (C282Y) into the Hfe locus, but otherwise leaves the gene intact. This mutation is identical to the disease-causing mutation in patients with hereditary hemochromatosis. Mice carrying each of the two mut ations were bred and analyzed. Homozygosity for either mutation results in postnatal iron loading. The effects of the null mutation are more severe th an the effects of the C282Y mutation. Mice heterozygous for either mutation accumulate more iron than normal controls. Interestingly, although liver i ron stores are greatly increased, splenic iron is decreased. We conclude th at the C282Y mutation does not result in a null allele. (C) 1999 by The Ame rican Society of Hematology.