DELETION OF EXON-3 OF THE INSULIN-RECEPTOR GENE IN A KINDRED WITH A FAMILIAL FORM OF INSULIN-RESISTANCE

Molecular scanning techniques, such as denaturing gradient gel electro phoresis (DGGE), greatly facilitate screening candidate genes for muta tions. We have used DGGE to screen for mutations in the insulin recept or gene in a family in which four of five daughters were affected by t ype A insulin resistance in association with acanthosis nigricans and hyperandrogenism. DGGE did not detect mutations in any of the 22 exons of the insulin receptor gene. Nevertheless, Southern blot analysis su ggested that there was a deletion of exon 3 in the other paternal alle le of the insulin receptor gene. Analysis of the father's cDNA confirm ed that exon 3 was deleted from mRNA molecules derived from one of his two alleles of the insulin receptor gene. Furthermore, the father was found to be hemizygous for a polymorphic sequence (GAC(Asp) at codon 234) in exon 3 that was not inherited by any of the five daughters. In stead, all five daughters inherited the paternal allele with the delet ion mutation. We did not detect mutations in the mother's insulin rece ptor gene. Furthermore, the clinical syndrome did not segregate with e ither of the mother's two alleles of the insulin receptor gene. Althou gh the youngest daughter inherited the mutant allele from her father, she was not clinically affected. The explanation for the incomplete pe netrance is not known. These results emphasize the importance of speci fically searching for deletion mutations when screening candidate gene s for mutations. Furthermore, the existence of apparently asymptomatic carriers of mutations in the insulin receptor gene, such as the fathe r in the present study, suggests that the prevalence of mutations in t he insulin receptor gene may be higher than would be predicted on the basis of the observed prevalence of patients with extreme insulin resi stance.