PREVALENCE OF MUTATIONS IN THE INSULIN-RECEPTOR GENE IN SUBJECTS WITHFEATURES OF THE TYPE-A SYNDROME OF INSULIN-RESISTANCE

Mutations of the insulin receptor gene are a cause of the type A syndr ome of extreme insulin resistance. This study assessed the prevalence of such mutations in women with clinical features of the type A syndro me including ovarian hyperandrogenism, moderate-to-severe degrees of i nsulin resistance, and acanthosis nigricans. We studied 22 unrelated w omen with insulin resistance (fasting insulin >300 pM [50 mu U/ml] and /or peak during an oral glucose tolerance test (OGTT) >1,800 pM [300 m u U/ml]), acanthosis nigricans, and the polycystic ovary syndrome (hyp erandrogenemia, oligoamenorrhea, and hirsutism). Two insulin-resistant probands with congenital generalized lipodystrophy and one male proba nd with severe insulin resistance also were included in the study. Sou thern blotting experiments were performed to exclude gross gene deleti ons, insertions, or rearrangements. Exons 2-22 of the insulin receptor gene were polymerase chain reaction (PCR) amplified from genomic DNA and screened for nucleotide variation using single-strand conformation polymorphism (SSCP). No nucleotide variation between study subjects w as detected in exons 4-6, 10-12, 15, 16, 18, 19, or 21. Sequencing of amplified DNA revealed that SSCP variants in exons 2, 3, 8, 9, and 17 corresponded to known silent polymorphisms within the coding region. V ariants in exons 2, 9, 13, and 14 were caused by novel silent polymorp hisms; variants in exons 7 and 22 were caused by nucleotide substituti ons in flanking introns. One proband was found to have a heterozygous point mutation in exon 20 (CGG-->CAG, Arg(174)-->Gln) that involves th e intracellular receptor beta-subunit. Gln(1174) is a novel mutant of the insulin receptor tyrosine kinase domain and is a likely cause of d ominantly inherited insulin resistance. The mutation was present in an affected sister but was absent in the unaffected mother and 64 normal alleles. Two paternal aunts also are reportedly affected. The results of this study suggest that mutations at the insulin receptor locus ar e uncommon in insulin-resistant women with acanthosis nigricans and ov arian hyperandrogenism.