HEREDITARY HEMOCHROMATOSIS - GENERATION OF A TRANSCRIPTION MAP WITHINA REFINED AND EXTENDED MAP OF THE HLA CLASS-I REGION

Hereditary hemochromatosis, a common severe inherited disease, maps to the short arm of chromosome 6 close to the HLA-A locus. Recently, lin kage data on Italian and French populations confirmed this location, w hile a similar analysis on Australian and British populations located the gene closer to D6S105, a marker residing telomeric of HLA-A. To in crease our knowledge on the region of highest linkage disequilibrium i n our population and possibly to identify the disease gene, a 1.2-Mb d etailed physical and transcription map was generated, spanning the HLA class I region. Thirty-eight unique cDNA fragments, retrieved followi ng the hybridization of immobilized YACs to primary pools of cDNAs pre pared from RNA of fetal brain, adult brain, liver, placenta, and the C aCo2 cell line, were characterized. All cDNA fragments were positioned in a refined and extended map of the human major histocompatibility c omplex spanning from HLA-E to approximately 500 kb telomeric of HLA-F. The localization of known genes was refined, and a new gene from the RNA helicase superfamily was identified. Overall, 14 transcription uni ts in addition to the HLA genes have been detected and integrated in t he map. Thirteen cDNA fragments show no similarity with known sequence s and could be candidates for the disease, Their characterization and assessment for involvement in hemochromatosis are still under investig ation. Seven new polymorphisms, some tightly linked to the disease, we re also identified and localized. (C) 1996 Academic Press, Inc.