Lipoatrophic diabetes: genetic exclusion of the insulin receptor gene

Lipoatrophic diabetes (LD) is a syndrome with congenital or delayed onset, characterized by severe insulin resistance and generalized lipoatrophy. Using denaturing gradient gel electrophoresis and sequencing, we have investigated the contribution of defects in the insulin receptor (IR) gene in LD. First, we performed an association study between the IR gene and congenital lipoatrophy in two families with consanguineous parents and one or two affected children (patients D1, D2, and D3). Segregation analysis of intragenic polymorphisms excluded a linkage between the IR locus and the LD phenotype in both families. Second, we screened for mutations in all exons and splice site junctions of the IR gene from patients D1-D3 and 11 additional unrelated patients with congenital or delayed forms of LD. The IR sequence proved to be normal in all 14 subjects because nucleotide variations that we detected were silent. The relative levels of expression of the 2 alleles of the IR gene were evaluated by allele-specific oligonucleotide hybridization in cells from most of these patients, and no gross alteration was detected. Overall, these results provide the first clear evidence against the involvement of the IR gene in the pathogenesis of any clinical form of LD.