Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from $8.99

All prices are NET prices.

References

  1. 1.

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

  2. 2.

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

  3. 3.

    & 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).

  4. 4.

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

  5. 5.

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

  6. 6.

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

  7. 7.

    , , , & Proto-cadherins: a gene family expressed differentially in the mouse brain. Cell. Mol. Life Sci. 62, 1247–1259 (2005).

  8. 8.

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

  9. 9.

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

  10. 10.

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

  11. 11.

    , , , & OL-protocadherin is essential for growth of striatal axons and thalamocortical projections. Nat. Neurosci. 10, 1151–1159 (2007).

  12. 12.

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

  13. 13.

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

  14. 14.

    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).

  15. 15.

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

  16. 16.

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

  17. 17.

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

  18. 18.

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

  19. 19.

    , , , & Conservation of PCDHX in mammals; expression of human X/Y genes predominantly in brain. Mamm. Genome 11, 906–914 (2000).

  20. 20.

    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).

  21. 21.

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

  22. 22.

    , , , & Parallel Foxp1 and Foxp2 expression in songbird and human brain predicts functional interaction. J. Neurosci. 24, 3152–3163 (2004).

  23. 23.

    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).

  24. 24.

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

Download references

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).

Author information

Author notes

    • Leanne M Dibbens
    •  & Patrick S Tarpey

    These authors contributed equally to this work.

Affiliations

  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.

    • Leanne M Dibbens
    • , Kim Hynes
    • , Marta A Bayly
    • , Lucianne Vandeleur
    • , Cheryl Shoubridge
    • , Grant R Sutherland
    • , Kathryn Friend
    • , Marie Shaw
    • , Mark Corbett
    • , Eric Haan
    • , John C Mulley
    •  & Jozef Gécz
  2. School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia 5005, Australia.

    • Leanne M Dibbens
    • , Grant R Sutherland
    • , John C Mulley
    •  & Jozef Gécz
  3. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

    • Patrick S Tarpey
    • , Raffaella Smith
    • , Sarah Edkins
    • , Claire Stevens
    • , Sarah O'Meara
    • , Calli Tofts
    • , Syd Barthorpe
    • , Gemma Buck
    • , Jennifer Cole
    • , Kelly Halliday
    • , David Jones
    • , Rebecca Lee
    • , Mark Madison
    • , Tatiana Mironenko
    • , Jennifer Varian
    • , Sofie West
    • , Sara Widaa
    • , Paul Wray
    • , John Teague
    • , Ed Dicks
    • , Adam Butler
    • , Andrew Menzies
    • , Andrew Jenkinson
    • , Rebecca Shepherd
    • , P Andrew Futreal
    •  & Michael R Stratton
  4. School of Molecular & Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.

    • Kim Hynes
    • , Edwina Sutton
    • , Grant R Sutherland
    • , Paul Thomas
    • , Eric Haan
    • , John C Mulley
    •  & Jozef Gécz
  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.

    • Ingrid E Scheffer
    • , Samantha J Turner
    • , Christopher P Derry
    •  & Samuel F Berkovic
  6. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia.

    • Ingrid E Scheffer
  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.

    • Jamee Bomar
    •  & Daniel H Geschwind
  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.

    • James F Gusella
    • , Amos D Korczyn
    •  & Hyung-Goo Kim
  9. Department of Neurology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel.

    • Zaid Afawi
    • , Aziz Mazarib
    •  & Miriam Y Neufeld
  10. Department of Neurology, Schneider Children's Medical Center, Petaq Tikvah 49202, Israel.

    • Sara Kivity
  11. Metabolic Neurogenetic Clinic, Wolfson Medical Center, 62 HaLohamim Street, Holon 58100, Israel.

    • Dorit Lev
    •  & Tally Lerman-Sagie
  12. AstraZeneca, 1800 Concord Pike, Wilmington, Delaware 19803, USA.

    • Stephen Ryan
  13. Northern Ireland Regional Genetics Service, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, Northern Ireland, UK.

    • Shane McKee

Authors

  1. Search for Leanne M Dibbens in:

  2. Search for Patrick S Tarpey in:

  3. Search for Kim Hynes in:

  4. Search for Marta A Bayly in:

  5. Search for Ingrid E Scheffer in:

  6. Search for Raffaella Smith in:

  7. Search for Jamee Bomar in:

  8. Search for Edwina Sutton in:

  9. Search for Lucianne Vandeleur in:

  10. Search for Cheryl Shoubridge in:

  11. Search for Sarah Edkins in:

  12. Search for Samantha J Turner in:

  13. Search for Claire Stevens in:

  14. Search for Sarah O'Meara in:

  15. Search for Calli Tofts in:

  16. Search for Syd Barthorpe in:

  17. Search for Gemma Buck in:

  18. Search for Jennifer Cole in:

  19. Search for Kelly Halliday in:

  20. Search for David Jones in:

  21. Search for Rebecca Lee in:

  22. Search for Mark Madison in:

  23. Search for Tatiana Mironenko in:

  24. Search for Jennifer Varian in:

  25. Search for Sofie West in:

  26. Search for Sara Widaa in:

  27. Search for Paul Wray in:

  28. Search for John Teague in:

  29. Search for Ed Dicks in:

  30. Search for Adam Butler in:

  31. Search for Andrew Menzies in:

  32. Search for Andrew Jenkinson in:

  33. Search for Rebecca Shepherd in:

  34. Search for James F Gusella in:

  35. Search for Zaid Afawi in:

  36. Search for Aziz Mazarib in:

  37. Search for Miriam Y Neufeld in:

  38. Search for Sara Kivity in:

  39. Search for Dorit Lev in:

  40. Search for Tally Lerman-Sagie in:

  41. Search for Amos D Korczyn in:

  42. Search for Christopher P Derry in:

  43. Search for Grant R Sutherland in:

  44. Search for Kathryn Friend in:

  45. Search for Marie Shaw in:

  46. Search for Mark Corbett in:

  47. Search for Hyung-Goo Kim in:

  48. Search for Daniel H Geschwind in:

  49. Search for Paul Thomas in:

  50. Search for Eric Haan in:

  51. Search for Stephen Ryan in:

  52. Search for Shane McKee in:

  53. Search for Samuel F Berkovic in:

  54. Search for P Andrew Futreal in:

  55. Search for Michael R Stratton in:

  56. Search for John C Mulley in:

  57. Search for Jozef Gécz in:

Contributions

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.

Corresponding authors

Correspondence to Leanne M Dibbens or Jozef Gécz.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–3, Supplementary Note and Supplementary Table 1

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.149