Análise preditiva in silico de uma alteração inédita no gene do receptor de andrógenos encontrada em uma família com insensibilidade androgênica

Abstract

The Androgen Insensitivity Syndrome (AIS) was first reported in 1953 by Morris; it is defined as a rare condition with X-linked recessive inheritance and is understood to be the most common cause of Disorders of Sex Development (DSD) in individuals with a 46,XY karyotype. Phenotypically, the characteristics of this syndrome vary from female-like phenotypes, with the presence of testes, breast development, and lack of hair growth, to male phenotypes, being infertile and/or with gynecomastia. AIS results from impairments in the binding of the hormones testosterone (T) and dihydrotestosterone (DHT) to the Androgen Receptor (AR), a protein that functions as a transcription factor, regulating the genes involved in physiological processes related to the development of male sexual characteristics. The AR gene is located in the Xq11-12 region. The AR protein has 3 domains: the amino-terminal domain (N-terminal), responsible for transcriptional regulation; the DNA-binding domain, responsible for nuclear localization and AR binding to DNA sequences in androgen-responsive elements; and the carboxy-terminal ligand-binding domain (C-terminal), responsible for T and DHT binding and transactivation. The impact of previously undescribed alterations in the AR protein can be investigated through **in silico** predictive analysis, a tool that aids in understanding the effect of mutations on the protein. Therefore, the objective of this work was to analyze the effect of the p.Ala567Asp alteration on the AR protein using bioinformatics tools. The programs and sites used were: HGMD, ARDB Clinvar, Clustal Omega, Franklin, SIFT, PolyPhen-2, and Mutation Taster. The HGMD, ARDB, and Clinvar databases were used to confirm the novelty of the p.Ala567Asp alteration. Clustal Omega showed that the 567 region of the AR protein is highly conserved among the analyzed species, and alterations in this region are highly pathogenic. Franklin classified it as probably pathogenic. SIFT considered the alteration deleterious; PolyPhen-2 and Mutation Taster revealed it to be probably pathogenic. The p.Ala567Asp alteration, never described in the literature, was identified in a family with five individuals affected by the complete AIS (CAIS) phenotype and seven asymptomatic carriers. Predictive analyses are an important tool for understanding and correlating the genotype/phenotype relationship of pathogenic alterations not described in the literature and are performed quickly and at low cost. Through this study, we can infer that the p.Ala567Asp alteration is pathogenic and is related to the CAIS phenotype. Functional analysis of the altered AR protein can complement this study and provide further insights into this alteration.