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

Leanne M. Dibbens, Patrick S. Tarpey, Kim Hynes, Marta A. Bayly, Ingrid E. Scheffer, Raffaella Smith, Jamee Bomar, Edwina Sutton, Lucianne Vandeleur, Cheryl Shoubridge, Sarah Edkins, Samantha J. Turner, Claire Stevens, Sarah O'Meara, Calli Tofts, Syd Barthorpe, Gemma Buck, Jennifer Cole, Kelly Halliday, David JonesRebecca Lee, Mark Madison, Tatiana Mironenko, Jennifer Varian, Sofie West, Sara Widaa, Paul Wray, John Teague, Ed Dicks, Adam Butler, Andrew Menzies, Andrew Jenkinson, Rebecca Shepherd, James F. Gusella, Zaid Afawi, Aziz Mazarib, Miriam Y. Neufeld, Sara Kivity, Dorit Lev, Tally Lerman-Sagie, Amos D. Korczyn, Christopher P. Derry, Grant R. Sutherland, Kathryn Friend, Marie Shaw, Mark Corbett, Hyung Goo Kim, Daniel H. Geschwind, Paul Thomas, Eric Haan, Stephen Ryan, Shane McKee, Samuel F. Berkovic, P. Andrew Futreal, Michael R. Stratton, John C. Mulley, Jozef Gécz

Research output: Contribution to journalArticlepeer-review

364 Scopus citations


Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.

Original languageEnglish
Pages (from-to)776-781
Number of pages6
JournalNature Genetics
Issue number6
StatePublished - Jun 2008
Externally publishedYes


FundersFunder number
Australian National Health and Medical Research Council400121
National Institute of Mental Health U.S.R01 MH 64547
Thyne-Reid Charitable Trusts
National Institutes of Health
National Institute of Mental HealthR01MH064547
National Institute of General Medical SciencesP01GM061354
National Institute of Child Health and Human DevelopmentNO1-HD-4-3383, NO1-HD-4-3368
University of Maryland
Wellcome Trust


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