Complete mutation scan of the human Fas ligand gene: linkage studies in Type I diabetes mellitus families.
OBJECTIVE
Type I (insulin-dependent) diabetes mellitus is the result of a T-cell regulated selective destruction of pancreatic beta cells. There is evidence that the apoptosis inducing T-cell effector, Fas ligand (FasL) could be involved in the pathogenesis of Type I diabetes, probably because FasL-mediated apoptosis is important in maintaining peripheral self-tolerance and in down-regulating an immune response. We therefore evaluated the human FasL gene FASL on chromosome 1q23 as a candidate susceptibility gene for Type I diabetes.


METHODS
The entire FASL (promoter, exons 1-4 and 3'UTR) was scanned for polymorphisms using single strand conformational polymorphism-heteroduplex analysis and direct sequencing.


RESULTS
We identified two novel polymorphisms, a g-C843T and a g-A475T, in a negative regulatory region of the promoter. A Danish Type I diabetes family collection of 1143 subjects comprising 257 families (420 affected and 252 unaffected offspring) was typed for the g-C843T polymorphism and for a FASL microsatellite. Haplotypes were established and data were analysed using the extended transmission disequilibrium test.


CONCLUSIONS
We found no overall evidence for linkage in the presence of association of the FASL polymorphism to Type I diabetes and conclude that FASL does not contribute to the genetic susceptibility to Type I diabetes.
Nolsøe
R L
RL
: Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark.
Kristiansen
O P
OP
Larsen
Z M
ZM
Johannesen
J
J
Pociot
F
F
Mandrup-Poulsen
T
T
D019943:Amino Acid Substitution; D001483:Base Sequence; D017931:DNA Primers; D003718:Denmark; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005091:Exons; D053222:Fas Ligand Protein; D005260:Female; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D007438:Introns; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009679:Nuclear Family; D009692:Nucleic Acid Heteroduplexes / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic; D012016:Reference Values; D044465:White People / Q000235:genetics
D017931:DNA Primers; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D009692:Nucleic Acid Heteroduplexes