Exclusion of insulin receptor substrate 2 (IRS-2) as a major locus for early-onset autosomal dominant type 2 diabetes

We investigated whether variability at the insulin receptor substrate (IRS) -2 lotus plays a role in the etiology of early-onset autosomal dominant typ e 2 diabetes. By means of radiation hybrid mapping, Re placed the human IRS -2 gene on 13q at 8.6 cRays from SHGC-37358. Linkage between diabetes and t wo polymorphic markers located in this region (D13S285 and D13S1295) was th en evaluated in 29 families with early-onset autosomal dominant type 2 diab etes. Included were 220 individuals with diabetes, impaired glucose toleran ce, or gestational diabetes (mean age at diabetes diagnosis 36 +/- 17 years ) and 146 nondiabetic subjects. Overall, strongly negative logarithm of odd s (LOD) scores for Linkage with diabetes were obtained by multipoint parame tric analysis (LOD score -45.4 at D13S285 and -40.9 at D13S1295), No signif icant evidence of linkage was obtained under the hypothesis of heterogeneit y or by nonparametric methods. Fourteen pedigrees for which linkage could n ot be excluded (LOD score > -2.0) were screened for mutations in the IRS-2 coding region by dideoxy fingerprinting. However, no mutations segregating with diabetes could be detected in these families. These data indicate that IRS-2 is not a major gene for early-onset autosomal dominant type 2 diabet es, although a role of mutations in the promoter region cannot be excluded at this time.