Australian scientists have discovered that changes to a gene
involved in brain development can lead to testis formation and male
genitalia in an otherwise female embryo.
Lead Melbourne researcher Professor Andrew Sinclair, of the
Murdoch Childrens Research Institute and University of Melbourne,
said the breakthrough would improve diagnosis and clinical
management of patients with disorders of sex development (DSD).
These conditions occur when the testes or ovaries do not develop
properly in the embryo, causing genital abnormalities in one in
4500 babies.
The gene, called SOX3, sits on the X chromosome and is normally
involved in the development of the central nervous system and the
brain's pituitary gland. But, scientists found that mutations
affecting the SOX3 gene caused it to be abnormally turned on in the
embryonic gonad, leading to testis development in human DSD
patients and mice.
In males, testis development is regulated by an almost identical
gene on the Y chromosome known as SRY. Females have two X
chromosomes and therefore do not have an SRY gene.
"We were puzzled by how female embryos could develop testes
without the SRY gene," Professor Sinclair said.
"Surprisingly, we found that the SOX3 gene could substitute for
the SRY gene in XX female embryos, resulting in the development of
testes, male genitalia and a masculine appearance in these
patients."
Professor Sinclair said the discovery could explain one in five
undiagnosed XX DSD cases, which would help provide a diagnosis and
guide clinical management of patients in the future.
The discovery also gives scientists new insight into the
evolution of the SRY gene, which is thought to have evolved from
the SOX3 gene. It is believed that changes to the SOX3 gene such as
those seen in these DSD patients must have occurred millions of
years ago, causing the SOX3 gene to be turned on in the gonad and
initiate testis development. This mutated SOX3 gene evolved into
the Y-linked testis determining gene, SRY.
The study, published today by The Journal of Clinical
Investigation, was undertaken in collaboration with the University
of Adelaide, Women's and Children's Hospital, Adelaide, Prince
Henry's Institute for Medical Research, Melbourne, King Edward
Memorial Hospital, Perth, University of California, USA, and the
National Institute for Medical Research, UK.