Mechanisms of disease: Transcription factors in sex determination--relevance to human disorders of sex development.

Sex determination is the series of molecular events that direct the undifferentiated bipotential gonad to become either a testis or an ovary. In humans, disruption of this process results in intersexuality, also referred to as disorders of sex development (DSD). Despite the discovery of the sex-determining gene SRY (sex-determining region Y) 15 years ago, the molecular mechanisms of sex determination remain poorly understood. Analysis of clinically relevant mutations of sex-determining genes in individuals with DSD has provided considerable insight into the function of these genes. The majority of disorders of sex determination with known causes are explained by mutations in one of three transcription factors at the core of the sex-determining pathway: SRY, SOX9 (SRY-box 9) and NR5A1 (nuclear receptor subfamily 5, group A, member 1). These mutations either affect the level of protein available at its nuclear site of action (via changes in regulatory sequences, deletions, non-sense mutations or mutations in nuclear localization sequences), or alter the structure of the protein (via modifications of binding or bending activity, or of interactions with other proteins). Deciphering the functional diversity of the mutations affecting the sex-determining pathway has immediate clinical impact on the diagnosis, outcome studies and classification of patients with DSD.