Prediction of the Structure and Mutations Instability of the Med12 Exon2 Gene in Uterine Fibroids in Senegalese Women

Abstract

Uterine fibroids are benign proliferations of slow evolution. They are associated with significant morbidity and constitute a real public health problem. Despite the large-scale medical and financial burden posed by uterine fibroids, the functional roles of the various factors and genes involved in their etiology and growth remain unclear. This shows a great need to undertake a study that would evaluate the molecular features of uterine fibroids. It is in this context that our study is based on 50 Senegalese women with uterine fibroids. Samples of tumour tissue and blood were taken from each patient. After sequencing, the raw data was submitted to the Mutation Surveyor software version 5.0.1. Pathogenicity of mutations was evaluated with Polyphen software. To better understand the functional impact of missense mutations at the three-dimensional level, we simulated the structure of the protein by the ab-initio method using the I-Tasser web server. After cleaning, correcting and aligning the sequences with the BioEdit software version 8.0.5, the amino acid frequencies for the blood and tumour tissue samples were retrieved with the MEGA7 software. To see if there is a difference in the distribution of each amino acid between blood and tumour tissue, the average comparison test was performed with the R software version 3.3.1. Our results showed the presence of mutations of the MED12 gene only in tumour tissues. All mutations are predicted to be deleterious. In comparison to the reference sequence, all the mutations show a conformational change in the 3D structure of the MED12 protein. In addition, the mutations p. Q43P, p. G44S, p. G44D, p. G44R, p. F45V, p. K60M give proteins of α-β structure different from the reference sequence which has an α structure. All mutations alter the predicted function of the MED12 protein, which further suggests their involvement in the pathobiology of uterine fibroids in Senegalese women. With regard to amino acid frequencies, the comparison of means between blood and tumour tissue samples shows different distributions for amino acids such as cysteine, aspartic acid, glycine, histidine, leucine, arginine and serine. The results obtained make it possible to better understand the molecular mechanisms involved in the etiology of uterine fibroids. They allow glimpsing applications for the screening of populations at risk, for a non-invasive diagnosis or even for preventive or curative treatment.