Journal Article

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

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

2008

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Agriculture / Amino acids / Animal Genetics and Genomics / Animals / Autism / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Brain - growth & development / Brain - metabolism / Brain - pathology / Cadherins - genetics / Cancer Research / Case-Control Studies / Cell adhesion & migration / Chromosomes / Chromosomes, Human, X / Codon, Nonsense - genetics / Cognition disorders / Cognition Disorders - genetics / Cognition Disorders - pathology / Cognitive ability / Complications and side effects / Diagnosis / Epilepsy / Epilepsy - genetics / Epilepsy - pathology / Female / Fibroblasts - cytology / Fibroblasts - metabolism / Fundamental and applied biological sciences. Psychology / Gene Expression Regulation, Developmental / Gene Function / Gene mutations / Genes, X-Linked - genetics / Genetic aspects / Genetic linkage / Genetics of eukaryotes. Biological and molecular evolution / Genomic Imprinting / Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy / Human Genetics / Humans / In Situ Hybridization / Intellectual disabilities / Learning disabilities / letter / Male / Medical research / Medical sciences / Mental disorders / Mice - embryology / Mutation / Mutation, Missense - genetics / Nervous system (semeiology, syndromes) / Neurology / Pedigree / Phenotype / Protocadherins / Reverse Transcriptase Polymerase Chain Reaction / Risk factors / RNA, Messenger - genetics / RNA, Messenger - metabolism / Skin - cytology / Skin - metabolism / Tissues / X-Linked Intellectual Disability - genetics / X-Linked Intellectual Disability - pathology