Genetic Mechanisms Underlying 46,XY DSD with Gonadal Dysgenesis

Genetic changes in key sex-determining genes lead to 46,XY disorders of sex development (DSD) in humans. Loss-of-function mutation in the sex-determining region on Y (SRY), steroidogenic factor 1 (SF1), and SRY-Box gene 9 (SOX9) genes causes varying phenotypic changes ranging from complete syndromic gonadal dysgenesis to isolated hypospadias. Similarly, gain of function of dosage-sensitive sex reversal adrenal hypoplasia congenita on X gene 1 (DAX1) through duplications within the Xp21 region also affects typical testicular determination, together demonstrating the critical roles these genes play in determining sex. The molecular mechanisms through which these transcription factors act during sex determination are poorly understood and our current efforts aim at delineating the complex interactions that fail due to mutation or deletion in human DSD.