Complete molecular scanning of the human Fas gene: mutational analysis and linkage studies in families with type I diabetes mellitus. The Danish Study Group of Diabetes in Childhood and The Danish IDDM Epidemiology and Genetics Group.
OBJECTIVE
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.


CONCLUSIONS
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.
Nolsøe
R L
RL
Steno Diabetes Center, Gentofte, Denmark.
Kristiansen
O P
OP
Sangthongpitag
K
K
Larsen
Z M
ZM
Johannesen
J
J
Karlsen
A E
AE
Pociot
F
F
Nerup
J
J
Verge
C F
CF
Mandrup-Poulsen
T
T
D000328:Adult; D002648:Child; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D017931:DNA Primers; D003718:Denmark; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005091:Exons; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D009679:Nuclear Family; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D044465:White People; D019014:fas Receptor / Q000235:genetics*
D017931:DNA Primers; D019014:fas Receptor