LIPOATROPHIC DIABETES - GENETIC EXCLUSION OF THE INSULIN-RECEPTOR GENE

Lipoatrophic diabetes (LD) is a syndrome with congenital or delayed on set, characterized by severe insulin resistance and generalized lipoat rophy. Using denaturing gradient gel electrophoresis and sequencing, w e have investigated the contribution of defects in the insulin recepto r (IR) gene in LD. First, we performed an association study between th e LR gene and congenital Lipoatrophy in two families with consanguineo us parents and one or two affected children (patients D-1, D-2, and D- 3). Segregation analysis of intragenic polymorphisms excluded a linkag e between the IR locus and the LD phenotype in both families. Second, are screened for mutations in all exons and splice site junctions of t he IR gene from patients D-1-D-3 and 11 additional unrelated patients with congenital or delayed forms of LD. The IR sequence proved to be n ormal in all 14 subjects because nucleotide variations that we detecte d were silent. The relative levels of expression of the 2 alleles of t he IR gene were evaluated by allele-specific oligonucleotide hybridiza tion in cells from most of these patients, and no gross alteration was detected. Overall, these results provide the first clear evidence aga inst the involvement of the IR gene in the pathogenesis of any clinica l form of LD.