Complete molecular scanning of the human Fas gene: mutational analysis andlinkage studies in families with Type I diabetes mellitus

Aims/hypothesis. The human Fas gene (FAS) on chromosome 10q24.1 encoding a cell surface receptor involved in apoptosis was evaluated as a candidate su sceptibility gene for Type I (insulin-dependent) diabetes mellitus. Apoptos is mediated by Fas is important in maintaining peripheral self-tolerance an d in down-regulating the immune response and could have a role in immune-me diated beta-cell destruction. Methods. We did a molecular scan of the entire human FAS (promoter, exons 1 -9 including exon-intron boundaries and the 3 'UTR) using single strand con formational polymorphism-heteroduplex analysis. Results. We identified 15 mutations, of which 11 are new. Of these a g-1194 A-->T and a g-295Ains give rise to alterations of transcription-factor-bind ing consensus sequences for c-Myb, SP-1 and NF-kappa B, respectively. A tot al of 1068 people from a Danish family collection comprising 138 Type I dia betic sib-pair families (289 affected and 121 unaffected offspring) and 103 Type I diabetic parent-offspring multiplex families (103 affected and 112 unaffected offspring) were typed for the three most frequent polymorphisms with high heterozygosity indices and for a FAS microsatellite, Haplotypes w ere established and data analysed using the extended transmission disequili brium test, ETDT. Conclusion/interpretation. We found no overall evidence for Linkage of the FAS polymorphisms to Type I diabetes. We conclude that it is unlikely that the Fas gene does contribute to genetic susceptibility for Type I diabetes.