FUNCTIONAL RESCUE OF PATHOGENIC VARIANTS IN AMH AND DHX37 GENES USING ZEBRAFISH MODEL

• Grant number: 25/07534-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2025
• End date: December 31, 2026
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Berenice Bilharinho de Mendonça
• Grantee: Marcela Gonçalves Meirelles
• Host Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 19/26780-9 - Molecular and epigenetic research on Differences in Sexual Development (DSD): impact of scientific diffusion on the relationship between science and society, AP.TEM

Abstract

Differences in Sex Development (DSD) are a heterogeneous group of conditions affecting gonadal development and spermatogenesis. Recent studies have identified mutations in DHX37 e AMH suggesting that these variants may impair essential mechanisms of sex determination and gonadal homeostasis. DHX37, an RNA helicase, plays a crucial role in testicular development, while AMH and its receptor AMHR2 regulate hormonal signaling for Müllerian duct regression and spermatogenesis maintenance. Evidence suggests that DHX37 may influence the AMH-AMHR2 pathway, linking RNA regulation to gonadal hormonal control. In this project, we will use the zebrafish model (Danio rerio) to functionally assess the pathogenic variants of these genes. Zebrafish embryos will be injected with mRNA from human wild-type (WT) and mutant variants, allowing us to analyze whether WT versions can rescue the phenotypic and molecular defects caused by the mutations. Histological, morphological, and molecular analyses will be conducted to examine alterations in gonadal development, gene expression, and hormonal signaling. This study is expected to clarify whether DHX37 regulates the AMH-AMHR2 pathway, providing experimental evidence on the interaction between RNA helicases and hormonal signaling in sexual differentiation. Furthermore, the results may improve the molecular diagnosis of DSD and contribute to genetic counseling for patients, as well as expand knowledge on spermatogenesis regulation in vertebrates. As part of the dissemination of results, an educational outreach program will be implemented, promoting a hands-on course on the zebrafish model for public school students.