A genetic reason for testicular tissue developing in people with female chromosomes has been identified.
Scientists at the Francis Crick Institute, London and the Institut Pasteur, Paris, France have identified that the cause of testis formation in people with female chromosomes may be due to an altered interaction between the mutated WT1 gene and beta-catenin protein.
'There are still many unknowns when it comes to the development of sexual organs. And for some patients with differences in their sexual development, and their families, the condition can be confusing and upsetting' Dr Anu Bashamboo, group leader at the Institut Pasteur, said. 'Understanding the underlying cause of sexual differences could help make it easier to identify hard-to-diagnose conditions and help families and doctors make more informed treatment and management decisions.'
Differences in sexual development (DSD) are a group of about 60 complex genetic conditions. DSD is estimated to occur in one in 2500-4000 children born each year, in which their biological sex (being male or female) is not clear. DSD is characterised where people with two X chromosomes, which is typical of females, have testicular tissue instead of ovaries, or genitals with a mixture of both testes or ovaries. Furthermore, they also do not have the Y chromosome gene (SRY), which is typically required for the formation of the male reproductive system.
The scientists analysed the DNA of 78 children with testicular DSD (TDSD) or ovotesticular DSD (OTDSD) and discovered that nine percent of the children had mutations in the Wilms' Tumour 1 (WT1) gene. Using human cell cultures they further discovered that these mutations interfered with whether male testes or female ovaries were formed. The mutations lead to suppression of a protein important to the development of ovaries: beta-catenin. With this protein suppressed, development of testicular tissue was favoured.
'It is often difficult to understand how these differences develop in humans because these changes take place early on in development. By the time they are diagnosed, often well after birth, it is too late to study them,' said lead author Dr Nitzan Gonen. Thus, the scientists recreated the WT1 gene mutation in mice to test their findings that the mutation leads to the differences in sex development. They discovered that mice which normally develop as females (with two X chromosomes), developed signs of male reproductive organ formation.
'The WT1 gene was well known to be important for testis development. It's really interesting that we've found it also plays a crucial role in development of ovaries,' says Professor Robin Lovell-Badge, of the Francis Crick Institute. 'It appears to have a dual function, creating one protein with parts that contribute to male and others to female development… Small changes in the balance of these two functions appears to alter the way sexual organs develop, even if our chromosomes are male or female.'
This research was published in Proceedings of the National Academy of Sciences USA.