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Hereditary hemochromatosis (HH) is a genetically heterogeneous disease. The HFE gene resides on chromosome 6 and its mutations account for the majority of HH cases in populations of northern European ancestry. Recently, two new types of hemochromatosis have been identified: Juvenile hemochromatosis (JH or HFE2), which maps to chromosome 1q21, and an adult form defined as HFE 3, which results from mutations of the TFR 2 gene, located at 7q22. We have performed a linkage study in five unrelated families of Greek origin with non-HFE hemochromatosis. Linkage at the chromosome 1q21 JH locus was detected in affected members with the use of polymorphic markers. Comparison of haplotypes between Greek and Italian JH patients revealed the presence of a common haplotype. However, the fact that many other haplotypes carrying the JH defect were observed in the two populations indicates that the respective mutations may have occurred in different genetic backgrounds. We suggest that hemochromatosis patients without HFE mutations should be evaluated for other possible types of hemochromatosis since hemochromatosis type 3 (HFE3) has a clinical appearance similar to HFE 1, and JH may have a late onset in some cases.

A family was studied in which two inherited defects of the non-alpha-globin cluster segregate: Greek hereditary persistence of fetal hemoglobin (HPFH) and beta-thalassemia. Fragments of the non-alpha-globin cluster from two patients were cloned in cosmid and phage lambda vectors, and assigned to either the HPFH or beta-thalassemic chromosome on the basis of the demonstration of a polymorphic BglII site in the HPFH gamma-globin cluster. The thalassemic beta-globin gene carries a mutation at nucleotide 1 of the intervening sequence I, known to cause beta zero-thalassemia; the beta-globin gene from the HPFH chromosome is entirely normal, both in the intron-exon sequence and in 5' flanking regions required for transcription. As the compound HPFH/beta-thalassemia heterozygote synthesizes HbA, these data prove that the HPFH beta-globin gene is functional, although at a decreased rate; its lower activity is likely to be due to a distant mutation. The HPFH A gamma-globin gene shows only two mutations: a T----C substitution in the large intervening sequence (responsible for the BglII polymorphic site) and a C----T substitution 196 nucleotides 5' to the cap site; the 5' flanking sequence is normal up to -1350 nucleotides upstream from the gene. Circumstantial evidence suggests that the mutation at -196 may be responsible for the abnormally high expression of the A gamma-globin gene.