Transferrin receptor-2 (TFR2) mutation Y250X in Alabama Caucasian and African American subjects with and without primary iron overload

Most cases of hemochromatosis are associated with mutations of the HFE gene on Ch6p. In southern Italy and central Alabama, the percentages of patient s with hemochromatosis who have "atypical" HFE genotypes (defined as lack o f C282Y homozygosity, C282Y/H63D compound heterozygosity, or H63D homozygos ity) are relatively great. A mutation of the transferrin receptor-2 gene (T FR2; exon 6, nt 750 C --> G, replaces TAC with stop signal TAG; Y250X) on C h7q22 was recently identified in two Sicilian families with HFE mutation-ne gative hemochromatosis. We wanted to estimate the frequency of this mutatio n in persons from central Alabama. We evaluated Caucasian hemochromatosis p robands with atypical HFE genotypes and African Americans with primary iron overload. We also studied control Caucasians, including persons of souther n Italian/Sicilian heritage, and control African Americans. Analysis of gen omic DNA was performed using a PCR-sequence-specific priming assay and posi tive control specimens from Sicilian hemochromatosis subjects heterozygous and homozygous for Y250X. Among Alabama subjects, this allele was not detec ted in 113 Caucasians, including 21 hemochromatosis probands with atypical HFE genotypes and 92 normal control subjects (including 27 of southern Ital ian/Sicilian descent). In African Americans, Y250X was not detected in 20 i ndex cases with primary iron overload or in 274 unrelated control subjects. We conclude that Y250X is uncommon in Caucasians with hemochromatosis asso ciated with atypical HFE genotypes, in African Americans with primary iron overload, and in the general Caucasian and African American population subg roups in central Alabama. (C) 2001 Academic Press.