Endocrine Abstracts

Introduction: Extreme insulin resistance monogenic syndromes, including type A insulin resistance syndrome and congenital lipodystrophies, share some phenotypic characteristics with polycystic ovary syndrome (PCOS). These conditions have an increased risk for developing cardiovascular disease and diabetes mellitus. Thus, both an early diagnosis and a personalized management are required at clinical realm.

Objective: To assess the prevalence of mutations in the insulin receptor (INSR) and lamin A/C (LMNA) genes in women with functional ovarian hyperandrogenism and insulin resistance.

Material and methods: n: 242 women with functional ovarian hyperandrogenism (PCOS or idiopathic hyperandrogenism) and insulin resistance defined by a Matsuda-index (ISI) <3.5 and/or HOMA-IR> 3.2 were studied. Genetic analysis was performed with genomic DNA from total blood samples using the real-time polymerase chain reaction (PCR) technique with fluorescence TaqMan probes or by sequencing. Mutations described in the literature in INSR and LMNA genes were screened in all patients. In 49 extreme-insulin resistant patients, exons and adjacent intronic regions of INSR and LMNA genes were also studied by Denaturing High-Performance Liquid Chromatography (DHPLC), and positive results were confirmed by sequencing.

Results: Sequencing of amplified DNA revealed that found variants in exons 2, 8, 9, 12, 13 and 17 in INSR gene, and variants in exons 3, 5, 7 and 10 in LMNA gene were benign polymorphisms within the coding region. LMNA promoter −1030 C/T polymorphism, described as a putative genetic responsible for arterial stiffness in Japanese population, was detected in 17 subjects with CT genotype and in 4 with TT genotype. Two sister were found to have a patogenic heterozygous mutation in exon 8 (c.1444C>T, p.Arg482Trp) in LMNA gene, and the final diagnosis of Dunningan familial partial lipodystrophy was established. One proband with extreme insulin resistance was found to have a heterozygous mutation in exon 5 (c.1246C>T, p.Arg416*) in INSR gene. Currently, exons 19-22 of INSR gene are being processed.

Conclusions: The identification of monogenic insulin resistance syndromes is essential in patients with apparent functional ovarian hyperandrogenism. Molecular-genetic studies allow an early diagnosis and genetic counseling, and likely, improving their prognosis. Since most available treatments are not fully satisfactory, molecular studies may provide potential novel therapeutic targets.