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Analysis of SOX9 gene expression regulatory region in pacients with DDS 46,XY caused by gonadal development dysfunction or without an determinate origin

Grant number: 13/05173-0
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): May 01, 2013
Effective date (End): December 31, 2013
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Elaine Maria Frade Costa
Grantee:Marina Alves Fanelli
Home Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil


For the male sex definition there are two consecutive and complementary steps involved: the sexual determination and the sexual differentiation, which include all the processes that result in the male or female phenotype definition. Several genes are involved in these processes, like the SOX9, which is considered essential to the testicular differentiation and to the definition of the male sex. It is known that SOX9 interacts with other important genes of the complex gonadal determination genic waterfall and it is also one of the main candidates to be the target of SRY gene. Nevertheless, inactivate mutations in the SOX9 codifier region were found only in the patients with 46, XY sexual reversion associated with campomelic dysplasia, which is distinguished for provoking multiple skeletal malformations. At the top of SOX9 gene there is a region of approximately 3kb, called "TES", where there is a central element with 1,4 kb of extension: the TESCO region. TESCO is composed by a specific-testicular regulatory sequence of SOX9 expression. In the Unit of Development Endocrinology of HC-FMUSP there are 75 patients who have sexual development disturbs caused by gonadal development anomalies or by an indeterminate cause. Many genes of these patients were analysed, but no mutations were found and none of them present associated diseases. Considering these facts, this paper aims to identify the 46,XY DSD etiology of these patients through the molecular study of the TESCO region. TESCO is considered the SOX9 testicular-specific promoter region and mutations in it can determinate the expression decrease of this gene, leading to testicular development modifications.