Dysregulation of a key testis gene implicated in disorders of sex development

Lead researcher

Dr Rajini Sreenivasan, Dr Louisa Ludbrook

Main finding

Children born with a disorder of sex development (DSD) may differ from typical males or females in their chromosomes, hormones or reproductive organs, sometimes resulting in infertility or gonadal cancer. DSDs are the most common birth defect and yet, most cases are unexplained genetically. Mutations in a gene called SF-1 often lead to DSDs. Our study has found that SF-1 mutants show compromised activity on a genetic enhancer that turns on a key testis development factor SOX9.


Centre for Endocrinology and Metabolism

Research group

Sex Determination and Gonadal Development


Dr Rajini Sreenivasan, Dr Louisa Ludbrook, Brett Fisher, Dr Faustine Declosmenil, Dr Kevin C. Knower, Brittany Croft, Dr Anthony D. Bird, Janelle Ryan, Dr Anu Bashamboo, Prof Andrew H. Sinclair, Prof Peter Koopman, Prof Ken McElreavey, Dr Francis Poulat, Prof Vincent R. Harley

Journal and article title

Most surprising

SF-1 mutants not only altered SOX9 enhancer activity. Many SF-1 mutants analysed were abnormally located within cells. The mutations were also found to cause changes in SF-1 protein structure that could affect its function. We also found that SF-1 mutants that resulted in more severely compromised SOX9 enhancer activity were more frequently associated with more severe DSD symptoms.

Future implications

When SOX9 level is too low, testicular development can be disrupted, leading to DSDs. Our study may therefore implicate altered SF-1-mediated production of SOX9 in DSDs. Understanding the genetic mechanisms that underlie DSDs has provided much needed answers as to how DSDs arise and will enable improved diagnosis and clinical management.

Disease/health impact

Disorders of sex development