Hereditary hemochromatosis: Generation of a transcription map within a 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 HIA-A locus. Recently, linkage data on Italian and French populations confirmed this location, while a similar analysis on Australian and British populations located the gene closer to D6S105, a marker residing telomeric of HLA-A. To increase our knowledge on the region of highest linkage disequilibrium in our population and possibly to identify the disease gene, a 1.2-Mb detailed physical and transcription map was generated, spanning the HIA class I region. Thirty-eight unique cDNA fragments, retrieved following the hybridization of immobilized YACs to primary pools of cDNAs prepared from RNA of fetal brain, adult brain, liver, placenta, and the CaCo-2 cell line, were characterized. All cDNA fragments were positioned in a refined and extended map of the human major histocompatibility complex spanning from HLAE to approximately 500 kb telomeric of HIA-F. The localization of known genes was refined, and a new gene from the RNA helicase superfamily was identified. Overall, 14 transcription units in addition to the HLA genes have been detected and integrated in the map. Thirteen cDNA fragments show no similarity with known sequences and could be candidates for the disease. Their characterization and assessment for involvement in hemochromatosis are still under investigation. Seven new polymorphisms, some tightly linked to the disease, were also identified and localized.