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Transcriptome and whole exome sequencing to elucidate different phenotypes of disorders of sexual development in 46,xy patients

Grant number: 20/13421-8
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): November 01, 2021
Effective date (End): October 31, 2022
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal researcher:Gil Guerra Júnior
Grantee:Helena Fabbri Scallet
Supervisor abroad: Olaf Hiort
Home Institution: Centro de Biologia Molecular e Engenharia Genética (CBMEG). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Research place: Universität zu Lübeck, Germany  
Associated to the scholarship:18/19445-6 - TRANSCRIPTOME AND WHOLE EXOME SEQUENCING TO ELUCIDATE DIFFERENT PHENOTYPES OF DISORDERS OF SEXUAL DEVELOPMENT IN 46,XY PATIENTS, BP.PD

Abstract

Conditions that present atypical genital and/or gonadal development leading to a disagreement among genetic, gonadal and phenotypic sex are classified as Disorders/Differences of Sex Development (DSD). Several genes are known to act in the pathways of sex determination and differentiation, such as: WT1, SRY, NR5A1, DMRT1, SOX9, GATA4, NR0B1, AMH, AR, SRD5A2, HSD17B3, among others. However, after screening for mutations in these genes, an important question arises: in cases for which mutations are identified, which are the biological effects they exert, and which is their real influence on the phenotype? This project will attempt to address these issues based on the results of previous studies. For that, three different approaches will be performed. First transcriptome data of gonadal biopsy material from patients who have variations at two nuclear receptors (AR and NR5A1) will be analyzed to investigate how these changes affect gene expression and regulation and correlate with the different phenotypes of the patients. Whole Exome Sequencing (WES) will be performed to search for further putative pathogenic variations that explain the different phenotypes. Functional impact of novel variations will be accesses thought in vitro reporter gene expression. This work may contribute to a better understanding of the molecular mechanisms that can explain the phenotype of some DSD patients.Data analysis from RNA-seq and WES and in vitro functional studies will be performed in collaboration with the Group for Medical Systems Biology and the Department of Pediatric and Adolescent Medicine, Division of Pediatric Endocrinology and Diabetes, respectively, both at University of Lübeck, Germany. The head of the DSD group in Lübeck is Professor Dr. Olaf Hiort, one of the most respected researches in the study of DSD in Europe. Professor Dr. Hauke Busch and Dr. Ralf Werner, will also assist the candidate during the internship, with their vast experience in RNA-seq analysis and molecular biology. (AU)

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