Mutations of the insulin receptor gene are a cause of the type A syndrome of extreme insulin resistance. This study assessed the prevalence of such mutations in women with clinical features of the type A syndrome including ovarian hyperandrogenism, moderate-to-severe degrees of insulin resistance, and acanthosis nigricans. We studied 22 unrelated women with insulin resistance (fasting insulin >300 pM [50 μU/ml] and/or peak during an oral glucose tolerance test (OGTT) > 1,800 pM [300 μU/ml]), acanthosis nigricans, and the polycystic ovary syndrome (hyperandrogenemia, oligoamenorrhea, and hirsutism). Two insulin-resistant probands with congenital generalized lipodystrophy and one male proband with severe insulin resistance also were included in the study. Southern blotting experiments were performed to exclude gross gene deletions, 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 was 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. Variants in exons 2, 9, 13, and 14 were caused by novel silent polymorphisms; variants in exons 7 and 22 were caused by nucleotide substitutions in flanking introns. One proband was found to have a heterozygous point mutation in exon 20 (CGG→CAG, Arg1174→Gln) that involves the intracellular receptor β-subunit. Gin1174 is a novel mutant of the insulin receptor tyrosine kinase domain and is a likely cause of dominantly 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 are uncommon in insulin-resistant women with acanthosis nigricans and ovarian hyperandrogenism.

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