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

被引:21
作者
Nolsoe, RL
Kristiansen, OP
Sangthongpitag, K
Larsen, ZM
Johannesen, J
Karlsen, AE
Pociot, F
Nerup, J
Verge, CF
Mandrup-Poulsen, T
机构
[1] Steno Diabet Ctr, DK-2820 Gentofte, Denmark
[2] St Vincents Hosp, Garvan Inst Med Res, Sydney, NSW 2010, Australia
[3] Univ New S Wales, Sydney Childrens Hosp, Sydney, NSW, Australia
关键词
genetics; candidate gene; apoptosis; tolerance; microsatellite; ALPS; c-Myb; SP-1; NF-kappa B;
D O I
10.1007/s001250051378
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 'UTR) using single strand conformational polymorphism-heteroduplex analysis. Results. We identified 15 mutations, of which 11 are new. Of these a g-1194A-->T and a g-295Ains give rise to alterations of transcription-factor-binding consensus sequences for c-Myb, SP-1 and NF-kappa B, 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.
引用
收藏
页码:800 / 808
页数:9
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