Molecular analysis of genes involved in sexual determination and differentiation in SRY-negative patients with the disorders of sex development 46,XX testicular e ovotesticular

• Grant number: 11/10089-3
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2011
• End date: February 28, 2014
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Elaine Maria Frade Costa
• Grantee: Elaine Maria Frade Costa
• Host Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Ibere Cauduro Soares ; Mirian Yumie Nishi ; Rosana Barbosa Silva ; Sorahia Domenice

Abstract

The embryo phenotypic sex is determined by the gonadal sex. The balance between the opposing pathways Fgf9/Sox9 and Wnt4/beta-catenin directs to a male or female fate during the sex determination and differentiation process. The expression of SRY and SOX9 is sufficient to induce testis development while the ovarian differentiation demands Wnt4/beta-catenin pathway activation. R-spondin 1 is essential for Wnt4 expression in XX gonads and acts as beta-catenin key regulator on female sexual determination. Mutational screening in our patients with 46,XX Testicular and Ovotesticular Disorders of Sex Development (DSD) excluded WNT4 and FGF9 mutations or SOX9 duplication. R-spondin 1 (RSPO1) mutations have recently been reported: a family with cases of SRY-negative 46,XX Testicular DSD (previously named as XX Sex Reversal or XX Male) and an isolated case of SRY-negative Ovotesticular DSD (previously named as True Hermaphrodite). These are the first description of human complete female-to-male sex reversal cases in the absence of the SRY associated with disruption of a single gene. Based on these evidences, the aims of this study are: search for mutations in RSPO in our patients with SRY-negative 46,XX Testicular and Ovotesticular DSD; study the expression of ²-catenin in case of RSPO1 mutation and determine the gonadal expression pattern of the genes involved in Wnt4/²-catenin and e Fgf9/Sox9 pathways (WNT4, RSPO1, FOXL2, CTNNB1, FGF9 e SOX9). (AU)