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Title: SOS1 is a candidate gene for idiopathic hirsutis      
Transcriptome or Gene expression
Expression profiling of androgen and insulin pathway regulating genes unveils SOS 1 as candidate gene for idiopathic hirsutism Background: Idiopathic Hirsutism (IH), defined as the presence of terminal hairs in females in a male-like pattern, affecting about 5% -15% of women, may result from the interaction between the androgen level and the sensitivity of the hair follicle to the androgen. The pathophysiology of IH is presumed to be linked to increased SRD5A activity, probably both isoenzyme types (SRD5A1 and SRD5A2) and generally related to an alteration in androgen receptor (AR) function. IH is often associated to metabolic syndrome, visceral obesity, dyslipidemia, insulin resistance, and hypertension.Methodology/Principal Findings: With the aim of identifying genes involved in the pathogenesis of this disorder, we investigated the expression profile of 190 genes involved in the androgen biosynthesis and metabolism, and other genes coding for products active in the insulin pathway in skin genital fibroblasts. For this purpose we selected from a cohort of 240 women affected with androgen excess syndrome a group of 52 idiopathic hirsute patients (22%) and we selected 8 of them with the higher grade of hirsutism (Ferriman & Gallway score >20) for the genetic studies comparing the data with 4 healthy women used as controls. The array gene signature in the IH patients identified 4 differentially expressed genes, 2 up-regulated and 2 down-regulated (FC≥± 1.5). Differentially expressed genes included products involved in insulin signalling while no androgens related genes were found altered in expression levels. We found that one of the over expressed transcript codes for the SOS1 gene product, which is overproduced in IH patients compared to controls. We did not identified any genomic variants or SNPs in the SOS1 promoter region and/or witin the 3’UTR with documented functional effects on SOS1 gene expression, although some variants in the 3’UTR seems to be potentially active in modulating the binding of transcription factors. Conclusions/Significance: In the cohort of women with androgen excess syndrome studied the 22% had neither hyperandrogenemia nor biochemical sign of hyperinsulinemia. We were able to demonstrate that SOS1 mRNA is over-expressed resulting in over production of SOS1 protein in IH patients. This suggests that an increase of SOS1 protein production could reflect a situation with an increased SOS1 activity function in hirsute patients. These findings propose a role for SOS1, in cooperation with other insulin pathway genes, in the pathogenesis of IH. Overall design: We used the microarray technology to study the expression profiles of 190 genes involved in the androgen biosynthesis and metabolism, and other genes coding for products active in the insulin pathway, in genital skin fibroblasts of 8 idiopathic hirsute women and 4 related controls. To reduce individual variation and other confounding events, such as spontaneous up- and down-regulation of genes, the patients and the controls were pooled into 2 distinct pools. The gene expression analysis have been just used to identify genes which expression profiles result alterated and which could represents new genes involved in the pathogenesis of hirsutism.
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