INSR gene mutations have been described in multiple individuals with extreme insulin resistance, but the INSR gene has not been implicated in familial NIDDM. We previously have screened members of 18 familial NIDDM pedigrees for mutations in exons encoding the tyrosine kinase domain of the INSR gene (exons 13–21) by SSCP. That analysis initially detected only patterns consistent with silent polymorphisms, but on direct sequence analysis of exon 17 we detected a Met-for-Val substitution at position 985 in 1/18 pedigrees. We confirmed the substitution by sequence analysis of subcloned, PCR-amplified DNA from two pedigree members and by hybridization to labeled primers for the normal and mutant sequences. We did not find the mutation in any other individuals. Pedigree members were typed for presence or absence of the Met985 substitution by hybridization of PCR-amplified exon 17 DNA to allele-specific oligonucleotide probes, and typing was confirmed by segregation of INSR haplotypes and by SSCP analysis. The substitution was present in 3 NIDDM individuals in 3 generations, including a lean individual with onset at age 24. The substitution was present in only 50% of NIDDM siblings in generation 2, however. To determine the clinical effect of the Met985 substitution, we compared the 5 nondiabetic pedigree members who carried the mutation with the 9 nondiabetic pedigree members without the mutation and with 266 members of other pedigrees. Fasting and 1-h postglucose insulin levels were not different between carriers and noncarriers (fasting, 71.4 pM vs. 74.5 pM; 1-h, 381 pM vs. 354 pM), even after correction for age, sex, and BMI. Both 1- and 2-h postglucose load glucose levels were higher (P < 0.05) among carriers relative to noncarriers, however (1-h, 9.2 mM vs. 6.55 mM; 2-h, 6.1 mM vs. 5.5 mM). Carriers also had significantly higher glucose levels when compared with 266 members of other pedigrees, after correction for age, weight, and sex (P < 0.05). These data suggest that although the Met985 substitution does not result in severe insulin resistance and has low penetrance with respect to expression of the NIDDM phenotype, it may represent a modifying factor if multiple loci predispose to diabetes in this pedigree. The identification of additional predisposing mutations and prospective studies of this pedigree will clarify the role of this insulin receptor substitution.

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