Letter abstract

Nature Genetics 40, 776 - 781 (2008)
Published online: 11 May 2008 | doi:10.1038/ng.149

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

Leanne M Dibbens1,2,14, Patrick S Tarpey3,14, Kim Hynes1,4, Marta A Bayly1, Ingrid E Scheffer5,6, Raffaella Smith3, Jamee Bomar7, Edwina Sutton4, Lucianne Vandeleur1, Cheryl Shoubridge1, Sarah Edkins3, Samantha J Turner5, Claire Stevens3, Sarah O'Meara3, Calli Tofts3, Syd Barthorpe3, Gemma Buck3, Jennifer Cole3, Kelly Halliday3, David Jones3, Rebecca Lee3, Mark Madison3, Tatiana Mironenko3, Jennifer Varian3, Sofie West3, Sara Widaa3, Paul Wray3, John Teague3, Ed Dicks3, Adam Butler3, Andrew Menzies3, Andrew Jenkinson3, Rebecca Shepherd3, James F Gusella8, Zaid Afawi9, Aziz Mazarib9, Miriam Y Neufeld9, Sara Kivity10, Dorit Lev11, Tally Lerman-Sagie11, Amos D Korczyn8, Christopher P Derry5, Grant R Sutherland1,2,4, Kathryn Friend1, Marie Shaw1, Mark Corbett1, Hyung-Goo Kim8, Daniel H Geschwind7, Paul Thomas4, Eric Haan1,4, Stephen Ryan12, Shane McKee13, Samuel F Berkovic5, P Andrew Futreal3, Michael R Stratton3, John C Mulley1,2,4 & Jozef Gécz1,2,4


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.

  1. Department of Genetic Medicine, Level 9 Rieger Building, Women's and Children's Hospital, 72 King William Road, North Adelaide, South Australia 5006, Australia.
  2. School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia 5005, Australia.
  3. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  4. School of Molecular & Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.
  5. Epilepsy Research Centre and Department of Medicine, University of Melbourne, Level 1 Neurosciences Building, Heidelberg Repatriation Hospital, Austin Health, Banksia Street, Heidelberg West, Victoria 3081, Australia.
  6. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia.
  7. Program in Neurogenetics and Neurobehavioral Genetics, Neurology Department and Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1769, USA.
  8. Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA and Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 0330, Boston, Massachusetts 02115, USA.
  9. Department of Neurology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel.
  10. Department of Neurology, Schneider Children's Medical Center, Petaq Tikvah 49202, Israel.
  11. Metabolic Neurogenetic Clinic, Wolfson Medical Center, 62 HaLohamim Street, Holon 58100, Israel.
  12. AstraZeneca, 1800 Concord Pike, Wilmington, Delaware 19803, USA.
  13. Northern Ireland Regional Genetics Service, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, Northern Ireland, UK.
  14. These authors contributed equally to this work.

Correspondence to: Leanne M Dibbens1,2,14 e-mail: leanne.dibbens@cywhs.sa.gov.au

Correspondence to: Jozef Gécz1,2,4 e-mail: jozef.gecz@adelaide.edu.au