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Genetic mechanisms underlying hypospadias
Summary
Hypospadias is one of the most common birth defects in humans affecting 1 in 250 boys in which the opening of the urethra is not at the end of the penis but along the shaft. We are exploring the genetic mechanisms underlying hypospadias by the generation of mouse models.
Description
In the 9 week-old human embryo, male and female external genitalia (genital tubercle, inner and outer genital folds) are indistinguishable from one another. In males, the genital tubercle grows and the inner genital folds fuse to form the penis, while fusion of the outer folds forms the scrotum.
In females, the genital tubercle remains small and becomes the clitoris, and the inner and outer genital folds remain separate and become the labia minora and labia majora, respectively. Abnormal genital fold fusion in males can cause hypospadias, a common condition in boys (1/250) in which the opening of the urethra is not at the end of the penis but along the shaft.
Patients with ATR-X syndrome display a wide range of genital abnormalities including hypospadias. ATRX is widely expressed throughout development and is thought to act as a transcription factor via its chromatin remodeling activity. To understand the etiology of hypospadias in the ATRX syndrome, we have generated a mouse model by conditional inactivation of the Atrx gene. Our data indicate that loss of ATRX leads to hypoplasia of the genital tubercle. Moreover, the urethral folds fail to fuse and consequently the urethral tube does not form. The analysis of this hypospadias mouse model will provide valuable insights into the genetic and cellular mechanisms underlying this condition.
Funding
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National Health and Medical Research Council
Outcomes
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Established a mouse model for hypospadias
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Established the etiology of hypospadias in ATR-X syndrome patients
Selected Publications
Bagheri-Fam, S., Argentaro, A., Svingen, T., Combes, A., Sinclair, A., Koopman, P. and Harley, V.R. (2011) Defective survival of proliferating Sertoli cells and androgen receptor function in a mouse model of the ATR-X syndrome. Human Molecular Genetics 20: 2213-2224
Tang, P., Argentaro, A., Pask, A.J., O’Donnell, L., Marshall-Graves, J., Familari, M. and Harley, V.R. (2011) Localisation of the chromatin remodelling protein, ATRX in the adult testis. Journal of Reproduction & Development 57: 317-321