A mutated gene that causes epilepsy and mental retardation only in women has been identified by scientists, in an unusual reversal of a genetic phenomenon that generally affects only men.

A rare condition called epilepsy and mental retardation limited to females (EFMR), which leads to seizures from infancy or early childhood and cognitive impairment, is caused when women inherit a defective copy of the PCDH19 gene, an Anglo-Australian research team has found.

The discovery is surprising because the PCDH19 gene is on the X chromosome, and genetic mutations on this chromosome usually cause disease only among males.

Females have two copies of the X chromosome, which generally protects them against X-linked mutations because they have a healthy back-up that can compensate. While they can be carriers of genetic conditions and pass them to their children, they do not normally fall ill themselves.

As males have only one X chromosome and Y chromosome, they have no back-up for genetic errors on the X, which can thus trigger severe diseases such as Duchenne muscular dystrophy and haemophilia.

The PCDH19 mutation, discovered by an international team led by Leanne Dibbins of the University of Adelaide, reverses this usual pattern.

It causes EFMR only when a defective copy is inherited by women on one of their X chromosomes, while men who inherit the same mutation on their solitary X chromosome are not affected.

The scientists, whose research is published in the journal Nature Genetics, suspect that the male Y chromosome may in some way be capable of compensating for the damage to the X, while the second female X chromosome cannot.

Professor Mike Stratton, a member of the team from the Wellcome Trust Sanger Institute near Cambridge, said: “The way in which this unusual disease is caused, particularly why it is expressed in women rather than men, remains a puzzle, but we are one step closer to unravelling the story.

“Identification of PCDH19 as the underlying gene will now allow diagnostic testing in families with the disease opening the possibility of prevention of further cases."

Dr Dibbens said: “This is the first time this type of gene has been found to be involved in epilepsy. “One of the most important discoveries we’ve made is that women in families affected by EFMR carry both a ‘good’ gene and a ‘bad’, mutated gene, while the men carry only the bad gene. For some reason, the men remain unaffected by the condition.

“We suspect this may have something to do with the male Y chromosome, but more research will be needed to find out exactly how or why.”

One hypothesis is that the genetic damage that the mutation causes results in part from having a mixture of brain cells with defective and normal genes. In women, one copy of the X chromosome is randomly switched off in every cell, while in men, the same X is active in all of them.

Another strong possibility is that a gene found on the male Y chromosome, but not on the X, can compensate for the problems caused by the PCDH19 mutation. A good candidate is a related gene called PCDH11Y: while this has a similar counterpart on the X called PCDH11X, it is slightly different and may not work in quite the same way.

The findings emerged from a study of seven families from Australia, the United States, Israel and Ireland. In one family, 23 women across five generations have suffered from EFMR.

The results also point towards the PCDH family of genes as a promising area for further investigation of epilepsy and other brain conditions, including autism and obsessive-compulsive disorder.

“With 100 related proteins involved in this gene family, this study could lead to many new areas of research, with the need to understand the role and function of each protein,” Dr Dibbens said.

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