A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis.
Bottom Line: Endometriosis is found in 5-15% of women of reproductive age and is more frequent in relatives of women with the disease.Activation of KRAS results in de novo endometriosis in mice, however, activating KRAS mutations have not been identified in women.We screened 150 women with endometriosis for a polymorphism in a let-7 microRNA (miRNA) binding site in the 3'-UTR of KRAS and detected a KRAS variant allele in 31% of women with endometriosis as opposed to 5% of a large diverse control population.
Affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.Show MeSH
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Mentions: To demonstrate that the increased level of KRAS protein seen in cultured hESC from subjects with the KRAS variant was in fact due to altered let-7 binding to the mutant LCS6, we introduced an siRNA construct designed to rescue let-7 activity by binding to the altered LCS6. Normal hESCs were co-transfected with a luciferase reporter construct carrying the variant LCS6, the siRNA or a siRNA negative control (Fig 3). Luciferase activity in the cells transfected with a reporter carrying the KRAS variant allele was approximately 30-fold greater than the activity from the reporter with the WT allele (relative luciferase activity: 0.1 ± 0.001 vs. 2.9 ± 0.05). The siRNA targeting the LCS6 variant RNA reduced the luciferase activity in the cells with the reporter containing the KRAS LCS6 variant by 70% (to 0.9 ± 0.13; p = 0.045).
Affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.