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.
We thank the members of the families studied for their participation and members of the International Genetics of Learning Disability (IGOLD) study for their collaboration. This work was supported by grants from the Australian National Health and Medical Research Council Program Grant 400121 (I.E.S., S.F.B., J.C.M. and J.G.), Thyne-Reid Charitable Trusts (L.M.D.) and the Wellcome Trust. We also acknowledge support to J.F.G. from US National Institutes of Health grant GM061354 and D.H.G. from US National Institute of Mental Health U.S. grant R01 MH 64547. We are grateful for access to the tissues used in these studies from the Developmental Brain and Tissue Bank at University of Maryland funded by the US National Institutes of Health (National Institute of Child Health and Human Development contracts NO1-HD-4-3368 and NO1-HD-4-3383).
Supplementary Figures 1–3, Supplementary Note and Supplementary Table 1