Gene mutation in rare form of epilepsy

Scientists have identified a genetic mutation responsible for a rare condition called epilepsy and mental retardation limited to females (EFMR), The Times reports. As the name suggests, this condition only affects females and causes seizures that start in infancy or early childhood, as well as cognitive impairment. The scientists identified a defect in the PCDH19 gene, which is found on the X chromosome.

Usually, females are resistant to diseases caused by mutations in genes on the X chromosome, because they have two copies of the X chromosome; if there is a mutation on one chromosome, the other chromosome compensates for the defect. Males, who have only one X chromosome, usually cannot compensate and they will be affected by the disease caused by the mutation. Surprisingly, this situation is reversed in EFMR, where women carrying the mutated gene are affected by the disease, but men are not. The newspaper reports that scientists think 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”.

This study provides compelling evidence that mutations in the PCDH19 gene cause the rare disease EFMR. Further studies will be needed to confirm that mutations in this gene are causing possible cases of EFMR in other families and to investigate why the disease affects women and not men.

Where did the story come from?

Dr Leanne Dibbens and colleagues from the University of Adelaide, the Wellcome Trust Sanger Institute and other centres in Australia, the UK, the US and Israel carried out this research. The study was funded by the Australian National Health and Medical Research Council, Thyne-Reid Charitable Trusts and the Wellcome Trust. Some of the authors also received funding from the US National Institutes of Health and of Mental Health. It was published in the peer-reviewed medical journal: Nature Genetics .

What kind of scientific study was this?

This was a genetic study which aimed to identify the mutation that causes the disease: epilepsy and mental retardation limited to females (EFMR). The mutation had previously been found to lie on a part of the X chromosome called Xq22.

The researchers identified six families with EFMR and looked at the sequence of 737 genes on the X chromosome in affected women from three of these families. They compared these sequences with the normal gene sequences and looked for mutations (changes in the sequence). Once they identified mutations within one gene, they then looked at the sequence of this gene in 87 other women with EFMR-like conditions (epilepsy with cognitive impairment), which had not yet been proven to be EFMR. Some of these women had other family members with a similar condition and some were the only known person with the condition in their family.

The researchers also looked at the sequence of this gene in 250 males with possible X-chromosome linked mental retardation and on 750 X chromosomes from men and women who did not have any form of epilepsy or mental retardation (controls). They then looked at where in the body this gene was active (producing protein) by testing samples of various human tissues and by looking at the brains of mice. They tested the effect the mutations had on how the gene worked in human skin cells. The researchers also looked at the activity of other related genes in human brain tissue.

What were the results of the study?

The researches identified mutations in the protocadherin 19 (PCDH19 ) gene in women with EFMR in all six families tested; they identified no mutations in any of the other genes tested. When they looked at the 87 other women with EFMR-like conditions, they also identified one other family with the mutation. In all of the families, all women who carried the mutation had EFMR, while those who didn’t carry the mutation did not have the disease. There were no mutations in this gene in the males with non-EFMR mental retardation or in control X chromosomes from people without mental retardation or epilepsy, which supported the fact that mutations in PCDH19 specifically cause EFMR.

All of the mutations in the PCDH19 gene in women with EFMR were predicted to stop the PCDH19 protein from functioning. Two of the mutations in the gene were shown to stop the gene from producing protein by prematurely breaking down the chemical messages sent from the gene to the protein-making machinery of the cells. The PCDH19 gene was mainly active in the human brain. The PCDH19 gene is a member of a family of related genes and researchers found that the PCDH11 gene, copies of which are found on the X and Y chromosomes, was also expressed in the human brain, but in different patterns in men and women.

What interpretations did the researchers draw from these results?

The researchers concluded that the PCDH19 gene is the first member of this protocadherin gene family to be linked to epilepsy and intellectual disability. They suggest that the differences between men and women could be related to how cells communicate with each other and that in men other protocadherin genes might be able to compensate for the loss of PCDH19 function.

What does the NHS Knowledge Service make of this study?

This study provides compelling evidence that mutations in the PCDH19 gene cause the rare disease EFMR. Further studies will be needed to confirm that mutations in this gene are causing EFMR in other families and to investigate why the disease affects women and not men.

Sir Muir Gray adds...

The term “genetic” covers many different types of relationship between our genetic inheritance and the occurrence of a disease. The fewer the number of genes involved, the more confident are we that the genetic mutation and the disease are linked in a way that could allow the information to be clinically useful. This is an example of a genetic link that might be useful.