11th May 2008

Mutant gene causes epilepsy, intellectual disability in women

A mutated gene has been discovered as the key behind families with epilepsy and mental retardation specific to women. The discovery shows that although men can carry the 'bad' gene, only women who carry it are affected.

The gene, called PCDH19, is found on the X chromosome: the expectation would generally be that in these families women, who have two X chromosomes, would be spared the effects of the mutation, because they have one normal copy of PCDH19 as well as the abnormal one. In contrast men, who have only one X chromosome, would be affected by the mutation in their only copy of PCDH19.

" 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 "

Prof Mike Stratton

Remarkably, the opposite is seen: women are affected and men are spared. The team propose that a gene on the Y chromosome may be protecting males.

Professor Michael Stratton of the Wellcome Trust Sanger Institute says: "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. However, 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."

The work has linked, for the first time, a large family of genes known as protocadherins with a condition known as "epilepsy and mental retardation limited to females" (EFMR).

Although a relatively uncommon disorder, the condition is hereditary, with successive generations of women affected. In just one of seven families studied across the world, 23 women were affected by the disorder across five generations. This discovery will now enable such families to benefit from genetic counselling, including screening for the genetic mutation at pregnancy.

The discovery, published today (Monday 12 May) in Nature Genetics, is a result of an international collaboration involving the Adelaide's Women's & Children's Hospital and the University of Adelaide, Australia, the Wellcome Trust Sanger Institute in Cambridge (UK), Wellcome Trust (UK) and many other collaborators in Melbourne, the United States, Ireland and Israel.

The research has been led in Australia by Dr Leanne Dibbens and Associate Professor Jozef Gecz from the Department of Genetic Medicine, Women's & Children's Hospital, and the Discipline of Paediatrics at the University of Adelaide and at the Wellcome Trust Sanger Institute by Professor Michael Stratton.

"This is the first time this type of gene has been found to be involved in epilepsy," Dr Dibbens says. "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."

Dr Dibbens says the gene involved in this discovery is important for cell-to-cell communication in the brain, and could also hold the key to better understanding related issues, such as autism and obsessive disorders.

"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," she says.

Clinically, the disorder EFMR was first described more than ten years ago, but the cause of EFMR has been unknown until now. Why females rather males are affected - as is usual for X chromosome associated disorders - makes this a unique disorder among the epilepsies and mental retardations.

For this study, seven families were studied in Australia, the United States, Israel and Ireland. The genetic mutation was discovered in each family.

Notes to Editors

Publication details

  • X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment.

    Dibbens LM, Tarpey PS, Hynes K, Bayly MA, Scheffer IE, Smith R, Bomar J, Sutton E, Vandeleur L, Shoubridge C, Edkins S, Turner SJ, Stevens C, O'Meara S, Tofts C, Barthorpe S, Buck G, Cole J, Halliday K, Jones D, Lee R, Madison M, Mironenko T, Varian J, West S, Widaa S, Wray P, Teague J, Dicks E, Butler A, Menzies A, Jenkinson A, Shepherd R, Gusella JF, Afawi Z, Mazarib A, Neufeld MY, Kivity S, Lev D, Lerman-Sagie T, Korczyn AD, Derry CP, Sutherland GR, Friend K, Shaw M, Corbett M, Kim HG, Geschwind DH, Thomas P, Haan E, Ryan S, McKee S, Berkovic SF, Futreal PA, Stratton MR, Mulley JC and Gécz J

    Nature genetics 2008;40;6;776-81


This work was supported by grants from the Australian National Health and Medical Research Council, the Wellcome Trust, Thyne-Reid Charitable Trusts, the National Institutes of Health and the National Institute of Mental Health.

The Women's and Children's Hospital

The Women's and Children's Hospital (WCH) Adelaide provides state of the art health care for women and children in Adelaide and South Australia. We are a world leader in many areas of endeavour. Each year, more than 30,000 people are admitted and around 4000 babies are born at the Hospital. In addition around 250,000 people come to the Hospital as outpatients. Research is a crucial investment in future health and the hundreds of research projects under way aim to prevent illness and disease and improve treatment options. The WCH is undertaking groundbreaking research in many fields including cytogenetics, immunology and lysosomal storage disorders.

The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.


The Wellcome Trust

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.


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