An altered gene which causes male embryos to develop female genitalia, has been identified in humans.

The discovery will lead to a faster and more accurate diagnosis of sex development disorders, says Andrew Sinclair at the Murdoch Children’s Research Institute, Australia.

One in 4500 babies have gene mutations which mean their testes or ovaries do not develop properly in the womb. This can lead to ambiguous genitalia and a physical appearance which doesn’t match their sex chromosomes. For example, “They may appear female even though they have male XY chromosomes,” says Sinclair.

Girls with the disorder may not develop breasts, and can have excessive hair and an enlarged clitoris. This spectrum of conditions is known as disorders of sex development (DSD). DSD can lead to emotional stress, infertility and an increased risk of cancer.


Sinclair and Harry Ostrer from New York University, compared the genes of 16 people from two families, who were affected by a particular type of DSD where male XY embryos develop female characteristics, including female genitalia and a feminine appearance.

“To date, we know of only a small number of genes that are involved in gonad development, and can only diagnose about 20 per cent of people with this type of DSD,” says Sinclair, leaving the remaining people “in a kind of limbo, as we cannot pinpoint the underlying cause of their condition”.

All 16 patients had an alteration in the MAP3K1 gene, whose function was previously unknown.

However, a common genetic alteration is not enough to link the gene to DSD. “If it’s not expressed at the right time and place, it can’t be a candidate,” says Sinclair.

So the team observed the equivalent gene in mice, to find out when and where it was active during development.

The gene turned out to be active precisely when mice testes are developing – 11.5 days after conception “In the mouse, it’s expressed early and in the right place to be playing a role in testis development,” says Sinclair.

According to Sinclair, MAP3K1 is part of a complex signalling pathway that leads to normal testes development.

Roger Short, a reproductive biologist at the University of Melbourne, Australia, is “completely convinced” that this gene is responsible for some cases of DSD.

“It’s a long genetic pathway to testis development,” he says. Pinpointing the genetic cause of an abnormality will help with diagnosis and treatment, says Short.

Journal reference: The American Journal of Human Genetics, DOI: 10.1016/j.ajhg.2010.11.003