DNA polymorphism related to the idiopathic hemochromatosis gene: evidence in a recombinant family

Abstract

The metabolic error involved in idiopathic hemochromatosis, as well as the underlying genetic defect remain unknown. It has, however, been recently shown that this genetic lesion occurs at a locus linked to the major histocompatibility complex, probably close to the HLA-A locus, and that the disease is recessively transmitted. Therefore, in a family where one subject has idiopathic hemochromatosis his HLA-identical siblings should also be affected. We present here the restriction polymorphism with two MHC class I probes and one DR beta probe in an exceptional family with three HLA-identical siblings: one (the proband) has a major form of idiopathic hemochromatosis, while the other two are free of any clinical or biochemical signs of the disease. The restriction patterns observed after DNA digestion by enzymes EcoRI, EcoRV, BglII, BamHI, PvuII, TaqI, HincII, and HindIII led to the conclusion that one of the proband's chromosome 6 had undergone two alterations: one, a deletion in the DR region, was revealed by missing fragments all correlated with DR5; the other was an unbalanced cross-over or a genetic conversion in the MHC class I region. This latter alteration was revealed by modifications in the patterns of high molecular weight HindIII bands which hybridize with probe pHLA2 and also by the absence of a HindIII fragment of 7.4 kb hybridized by another class I probe. This latter alteration most likely involved the hemochromatosis gene and could be the first step toward a molecular approach to this gene.

Genetic Hemochromatosis: Pathogenesis, Diagnosis, and Therapy

“…This led to the conclusion that the gene was located closer to the A than to the B locus. It remains unclear whether the gene for hemochromatosis maps between the A and B loci, as suggested by Edwards et al [14], or telomeric to the A locus [15]. The lat ter hypothesis is supported by a recent report by Jazwinska et al [16] who employed micro satellites (short tandem repeated sequences) identified on the short arm of chromosome 6 as a tool to localize the hemochromatosis gene.…”

Inherited Iron Overload

“…Such studies have included restriction enzyme studies of DNA from affected families seeking restriction fragment length polymorphisms which could provide markers for the disease. No defini· tive results are so far available despite some early promise (25).…”