Objective Idiopathic haemochromatosis, an autosomal recessive disorder of iron metabolism, is one of the most common genetic diseases in Europe. It is characterised by excessive iron absorption through the duodenal mucosa and progressive iron deposition in parenchymal organs, which results in the midlife onset of severe clinical complications, including cirrhosis, diabetes mellitus, cardiopathy, endocrine dysfunctions, and arthropathy. Patients who undergo early diagnosis and phlebotomy treatment before the development of organ damage have a normal life expectancy in contrast to those individuals who remain undiagnosed. A significant proportion of those latter individuals will indeed succumb to hepatocellular carcinoma or cardiac failure. The nature of the underlying defect is still unknown. HLA typing studies have shown an association between haemochromatosis and the HLA-A3 antigen. Subsequent analysis of affected pedigrees has demonstrated linkage between the putative haemochromatosis gene and HLA-class I genes on chromosome 6p. There is however no evidence that the gene lies close to HLA-A: recent work has suggested that allele 8 of the marker D6S105, subsequently mapped approximately 2000 kb telomeric to HLA-A, was a better marker for the disease than HLA-A3. Linkage disequilibrium data from Cardiff suggest that the gene may even lie telomeric to D6S105. With respect to physically localising the gene, investigators must still content with a candidate gene region spanning a total physical distance of at least 2000 kb. The objectives of the proposed work are: i) to narrow the size of the haemochromatosis candidate region on chromosome 6p to about 200 kb by isolating and physically mapping microsatellite markers spanning the region between MOG and D6S105 (and beyond if necessary), producing high resolution haplotypes across the disease locus for linkage disequilibrium mapping, ascertaining significant chromosomal abnormalities such as deletions or insertions in patients, as well as recombination events in families with multiple affected individuals; ii) to identify the gene responsible for haemochromatosis in this narrowed region by creating a contig of cosmids, identifying coding sequences by exon trapping, cDNA selection, and/or zoo blot, characterising the genomic structure of candidate genes and carrying out mutation analyses in patients. Fields of science medical and health sciencesclinical medicineendocrinologydiabetesnatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicinehepatologynatural sciencesbiological sciencesgeneticschromosomes Programme(s) FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998 Topic(s) 5.3 - Role of gene and gene products in disease aetiology and pathogenesis Call for proposal Data not available Funding Scheme CSC - Cost-sharing contracts Coordinator Centre National de la Recherche Scientifique Address Avenue de grande bretagne 31300 Toulouse France See on map EU contribution € 0,00 Participants (5) Sort alphabetically Sort by EU Contribution Expand all Collapse all IRCCS - OPSEDALE CASA SOLLIEVO DELLA SOFFERENZA Italy EU contribution € 0,00 Address Viale cappuccini 1 71013 San giovanni rotondo See on map THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE United Kingdom EU contribution € 0,00 Address Hills road addenbrooke's nhs trust 5 CB2 2QQ Cambridge See on map The Chancellor, Masters and Scholars of the University of Oxford United Kingdom EU contribution € 0,00 Address John radcliffe hospital headington OX1 2JD Oxford See on map UNIVERSITY OF TORINO Italy EU contribution € 0,00 Address Strada provinciale 142 10060 Airasca See on map University of Wales College of Medicine EU contribution € 0,00 Address See on map
