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

Abstract

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.

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Figure 1: Mutations in PCDH19 cause EFMR.
Figure 2: Structure and expression analysis of PCDH19.
Figure 3: Expression of Pcdh19 in the developing mouse CNS.
Figure 4: Expression of PCDH11X/Y and PCDH19 in midgestation developing human CNS.

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References

  1. Ryan, S.G. et al. Epilepsy and mental retardation limited to females: an X-linked dominant disorder with male sparing. Nat. Genet. 17, 92–95 (1997).

    Article  CAS  Google Scholar 

  2. Juberg, R.C. & Hellman, C.D. A new familial form of convulsive disorder and mental retardation limited to females. J. Pediatr. 79, 726–732 (1971).

    Article  CAS  Google Scholar 

  3. Fabisiak, K. & Erickson, R.P. A familial form of convulsive disorder with or without mental retardation limited to females: extension of a pedigree limits possible genetic mechanisms. Clin. Genet. 38, 353–358 (1990).

    Article  CAS  Google Scholar 

  4. Scheffer, I.E. et al. Epilepsy and mental retardation limited to females: an under-recognised disorder. Brain 131, 918–927 (2008).

    Article  Google Scholar 

  5. Wolverton, T. & Lalande, M. Identification and characterization of three members of a novel subclass of protocadherins. Genomics 76, 66–72 (2001).

    Article  CAS  Google Scholar 

  6. Maquat, L.E. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat. Rev. Mol. Cell Biol. 5, 89–99 (2004).

    Article  CAS  Google Scholar 

  7. Vanhalst, K., Kools, P., Staes, K., van Roy, F. & Redies, C. Proto-cadherins: a gene family expressed differentially in the mouse brain. Cell. Mol. Life Sci. 62, 1247–1259 (2005).

    Article  CAS  Google Scholar 

  8. Kim, S.Y. et al. Spatiotemporal expression pattern of non-clustered protocadherin family members in the developing rat brain. Neuroscience 147, 996–1021 (2007).

    Article  CAS  Google Scholar 

  9. Wu, Q. & Maniatis, T. A striking organization of a large family of human neural cadherin-like cell adhesion genes. Cell 97, 779–790 (1999).

    Article  CAS  Google Scholar 

  10. Yagi, T. & Takeichi, M. Cadherin superfamily genes: functions, genomic organization, and neurologic diversity. Genes Dev. 14, 1169–1180 (2000).

    CAS  Google Scholar 

  11. Uemura, M., Nakao, S., Suzuki, S.T., Takeichi, M. & Hirano, S. OL-protocadherin is essential for growth of striatal axons and thalamocortical projections. Nat. Neurosci. 10, 1151–1159 (2007).

    Article  CAS  Google Scholar 

  12. Ahmed, Z.M. et al. Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F. Am. J. Hum. Genet. 69, 25–34 (2001).

    Article  CAS  Google Scholar 

  13. Patel, S.D. et al. Type II cadherin ectodomain structures: implications for classical cadherin specificity. Cell 124, 1255–1268 (2006).

    Article  CAS  Google Scholar 

  14. Morishita, H. et al. Structure of the cadherin-related neuronal receptor/protocadherin-alpha first extracellular cadherin domain reveals diversity across cadherin families. J. Biol. Chem. 281, 33650–33663 (2006).

    Article  CAS  Google Scholar 

  15. Bauer, R. & Bosserhoff, A.K. Functional implication of truncated P-cadherin expression in malignant melanoma. Exp. Mol. Pathol. 81, 224–230 (2006).

    Article  CAS  Google Scholar 

  16. Arnold, A.P. Sex chromosomes and brain gender. Nat. Rev. Neurosci. 5, 701–708 (2004).

    Article  CAS  Google Scholar 

  17. Yang, X. et al. Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res. 16, 995–1004 (2006).

    Article  CAS  Google Scholar 

  18. Wieland, I. et al. Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome. Am. J. Hum. Genet. 74, 1209–1215 (2004).

    Article  CAS  Google Scholar 

  19. Blanco, P., Sargent, C.A., Boucher, C.A., Mitchell, M. & Affara, N.A. Conservation of PCDHX in mammals; expression of human X/Y genes predominantly in brain. Mamm. Genome 11, 906–914 (2000).

    Article  CAS  Google Scholar 

  20. Durand, C.M. et al. Expression and genetic variability of PCDH11Y, a gene specific to Homo sapiens and candidate for susceptibility to psychiatric disorders. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 141, 67–70 (2006).

    Article  Google Scholar 

  21. Takeichi, M. The cadherin superfamily in neuronal connections and interactions. Nat. Rev. Neurosci. 8, 11–20 (2007).

    Article  CAS  Google Scholar 

  22. Teramitsu, I., Kudo, L.C., London, S.E., Geschwind, D.H. & White, S.A. Parallel Foxp1 and Foxp2 expression in songbird and human brain predicts functional interaction. J. Neurosci. 24, 3152–3163 (2004).

    Article  CAS  Google Scholar 

  23. Wilson, L.D. et al. Developmentally regulated expression of the regulator of G-protein signaling gene 2 (Rgs2) in the embryonic mouse pituitary. Gene Expr. Patterns 5, 305–311 (2005).

    Article  CAS  Google Scholar 

  24. Gaitan, Y. & Bouchard, M. Expression of the δ-protocadherin gene Pcdh19 in the developing mouse embryo. Gene Expr. Patterns 6, 893–899 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

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).

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L.M.D. and P.S.T. contributed equally to this work. L.M.D. coordinated the project in concept and design, supervised molecular studies, managed collaborations, wrote the first draft of the manuscript and significantly edited successive manuscript drafts; P.S.T. supervised the X-chromosome gene sequencing and analysis; K. Hynes and M.A.B. carried out molecular studies. I.E.S., S.F.B., S.J.T., E.H., S.M., S.R., A. Mazarib, Z.A., M.Y.N., S.K., D.L., T.L.-S., A.D.K. and C.P.D. identified families and provided clinical information; R.S., S.E., C. Stevens, S.O., C.T., S.B., G.B., J.C., K. Halliday, D.J., T.M., J.V., S. West, S. Widaa, J.T., E.D., A.B., R.L., M.M., P.W., A. Menzies, A.J. and R.S. performed the X-chromosome gene sequencing and analysis of 737 genes. L.V. performed tissue culture work, J.B. and D.H.G. carried out and interpreted the human in situ hybridization analysis, K.F. performed and interpreted linkage analysis, M.S. and K. Hynes did X inactivation studies and their interpretation, and M.C. and C. Shoubridge contributed to the supervision of molecular and cell studies. H.-G.K. and J.F.G. contributed to segregation analysis. E.S. and P.T. performed and interpreted the mouse in situ hybridization analysis. I.E.S. and S.F.B. contributed to the project concept and coordinated families. E.H. and G.R.S. coordinated families. P.A.F. and M.R.S. coordinated the X-chromosome gene sequencing and analysis. J.C.M. and J.G. coordinated and supervised the project in concept and design, supervised molecular studies, managed collaborations and significantly edited successive drafts. All authors contributed to the discussion of the results and the preparation of successive manuscript drafts with the opportunity to comment critically and constructively.

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Correspondence to Leanne M Dibbens or Jozef Gécz.

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Supplementary Figures 1–3, Supplementary Note and Supplementary Table 1 (PDF 125 kb)

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Dibbens, L., Tarpey, P., Hynes, K. et al. X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat Genet 40, 776–781 (2008). https://doi.org/10.1038/ng.149

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