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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 publication

DOI

10.1038/ng.149

Type

Journal

Nature genetics

Publication Date

06/2008

Volume

40

Pages

776 - 781

Addresses

Department of Genetic Medicine, Level 9 Rieger Building, Women's and Children's Hospital, 72 King William Road, North Adelaide, South Australia 5006, Australia. leanne.dibbens@cywhs.sa.gov.au

Keywords

Brain, Chromosomes, Human, X, Fibroblasts, Skin, Animals, Humans, Mice, Epilepsy, Mental Retardation, X-Linked, Cadherins, RNA, Messenger, Codon, Nonsense, In Situ Hybridization, Case-Control Studies, Reverse Transcriptase Polymerase Chain Reaction, Pedigree, Cognition Disorders, Gene Expression Regulation, Developmental, Genomic Imprinting, Phenotype, Mutation, Missense, Female, Male, Genes, X-Linked