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

• Published in: Diabetologia 2000-06, Vol.43 (6), p.800-808
• Main Authors: NOLSØE, R. L, KRISTIANSEN, O. P, SANGTHONGPITAG, K, LARSEN, Z. M, JOHANNESEN, J, KARLSEN, A. E, POCIOT, F, NERUP, J, VERGE, C. F, MANDRUP-POULSEN, T
• Format: Article
• Language: English
• Subjects: Apoptosis; Biological and medical sciences; Cell death; Diabetes; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Homeostasis; Lymphocytes; Medical sciences; Mutation; Polymorphism; White people
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s001250051378

Aims/hypothesis. The human Fas gene (FAS) on chromosome 10q24.1 encoding a cell surface receptor involved in apoptosis was evaluated as a candidate susceptibility gene for Type I (insulin-dependent) diabetes mellitus. Apoptosis mediated by Fas is important in maintaining peripheral self-tolerance and in down-regulating the immune response and could have a role in immune-mediated 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 [variant prime]UTR) using single strand conformational polymorphism-heteroduplex analysis.¶Results. We identified 15 mutations, of which 11 are new. Of these a g-1194A[arrow right]T and a g-295Ains give rise to alterations of transcription-factor-binding consensus sequences for c-Myb, SP-1 and NF-kB, respectively. A total of 1068 people from a Danish family collection comprising 138 Type I diabetic 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 were established and data analysed using the extended transmission disequilibrium 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. [Diabetologia (2000) 43: 800-808]