Molecular scanning of the insulin receptor gene in women with polycystic ovarian syndrome.

Abstract

Polycystic ovary syndrome (PCOS) is a common disorder characterized by chronic anovulation and infertility, hyperandrogenaemia, and frequently insulin resistance. This study investigated whether mutations in the insulin receptor gene could explain the insulin resistance in subjects with PCOS. From a total of 108 women with PCOS, a subgroup of 24 were selected on the criteria of being in the upper quartile for insulin resistance as assessed by fasting serum insulin, insulin area under the curve following 75 g oral glucose tolerance test, and endogenous glucose disposal as a measure of insulin sensitivity. An additional five normal women were also investigated. The entire coding region of the insulin receptor gene, comprising of 22 exons, was amplified by the PCR using genomic DNA and then subjected to single-stranded conformation polymorphism (SSCP) analysis to screen for single-base DNA sequence changes. DNA sequencing revealed that SSCP variants were detected in regions encompassing exons 3, 6-8, 11, 13, 15, 17, and 22. SSCP variants in regions of exons 3, 6, 7, 11, 15 and 22 were caused by nucleotide substitutions within intronic regions flanking the exon. The considerable variation seen in the 5' intron of exon 3 was found to be caused by variation in the number of (ATTT, 8-11) and (TC, 10-13) short sequence repeats. SSCP variants in exons 8 (Asp519, Ala523), 13 (Asn 838), and 17 (Tyr984, His1058) were caused by known silent polymorphisms. Southern blotting experiments excluded major gene deletions, insertions, or rearrangements. We conclude that insulin resistance in subjects with PCOS is not commonly a consequence of missense or nonsense mutations in the insulin receptor gene.

The pathophysiology of polycystic ovary syndrome

“…The hypothesis for the existence of a postreceptor defect in insulin action in PCOS is also consistent with reports of molecular studies found no structural abnormality in the insulin receptor (Conway et al ., 1994;Sorbara et al ., 1994;Talbot et al ., 1996).…”

Genetic variation in exon 17 of INSR is associated with insulin resistance and hyperandrogenemia among lean Indian women with polycystic ovary syndrome

“…Other studies showed that the number and affinity of insulin receptor is not altered in PCOS but its tyrosine phosphorylation status and subsequent signaling is affected, suggesting the defect may lie in the b-chain (16,20). Studies to determine mutations in INSR failed to find any major variations; however, several polymorphisms were identified (21)(22)(23)(24)(25)(26)(27)(28). The most frequent of these were at exon 17, which encodes the partial tyrosine kinase domain containing the ATP binding site of INSR, important for its downstream signaling (21)(22)(23)(24)(25)(26)(27)(28).…”

“…Studies to determine mutations in INSR failed to find any major variations; however, several polymorphisms were identified (21)(22)(23)(24)(25)(26)(27)(28). The most frequent of these were at exon 17, which encodes the partial tyrosine kinase domain containing the ATP binding site of INSR, important for its downstream signaling (21)(22)(23)(24)(25)(26)(27)(28). Among these polymorphisms, a C/T SNP at His1058 in exon 17 has been reported to be significantly associated with PCOS in two independent studies in Caucasian and Chinese women (25,26).…”

Role of Allelic Variants Gly972Arg of IRS-1 and Gly1057Asp of IRS-2 in Moderate-to-Severe Insulin Resistance of Women With Polycystic Ovary Syndrome

“…PCOS is another good model to study influent genes, because in this complex disease, characterized by chronic anovulation and hyperandrogenism in women, insulin resistance is a major component (3,12). In common forms of PCOS, IR mutations have not been found, and linkage studies excluded IR and IRS-1 as major genes (13,14). To understand genetic determinants of insulin resistance, we investigated the effects of two variants of IRS-1 and IRS-2 in PCOS (n ϭ 53) with values (mean Ϯ SE) for homeostasis model assessment index for insulin resistance (HOMA IR ) twofold higher than the control population (1.56 Ϯ 0.034, n ϭ 102) ( Table 1).…”