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Mutations in DEPDC5 cause familial focal epilepsy with variable foci

Nature Genetics volume 45, pages 546–551 (2013)Cite this article

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Abstract

The majority of epilepsies are focal in origin, with seizures emanating from one brain region. Although focal epilepsies often arise from structural brain lesions, many affected individuals have normal brain imaging. The etiology is unknown in the majority of individuals, although genetic factors are increasingly recognized. Autosomal dominant familial focal epilepsy with variable foci (FFEVF) is notable because family members have seizures originating from different cortical regions1. Using exome sequencing, we detected DEPDC5 mutations in two affected families. We subsequently identified mutations in five of six additional published large families with FFEVF. Study of families with focal epilepsy that were too small for conventional clinical diagnosis with FFEVF identified DEPDC5 mutations in approximately 12% of families (10/82). This high frequency establishes DEPDC5 mutations as a common cause of familial focal epilepsies. Shared homology with G protein signaling molecules and localization in human neurons suggest a role of DEPDC5 in neuronal signal transduction.

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Figure 1: Pedigrees of families with FFEVF.
Figure 2: Location of the alterations in DEPDC5 detected in families with FFEVF and expression analysis of Depdc5 transcripts in mouse neural tissues.
Figure 3: Depdc5 protein localization in adult mouse brain.

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Acknowledgements

We thank the individuals with epilepsy and their families for participating in our research. We thank B. Johns and R. Schultz for technical assistance and M. Broli, F. Provini, S. Foote and K. Praveen for assistance with family studies. We thank the Leiden Genome Technology Centre (LGTC) for exome sequencing of family D1. This work was supported by the National Health and Medical Research Council of Australia (Program grant 628952 to S.F.B., I.E.S., L.M.D., P.Q.T. and J.G., Australia Fellowship 466671 to S.F.B., Senior Research Fellowship 508043 to J.G., Practitioner Fellowship 1006110 to I.E.S., Training Fellowship 1016715 to S.E.H. and Career Development Fellowship 1032603 to L.M.D.) and by the Center of Medical System Biology (CMSB) established by the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NGI/NWO) to A.M.J.M.v.d.M., the Netherlands Organization for Scientific Research (NWO, 940-33-030) and the Dutch National Epilepsy Fund (98-14). P.M.C.C. received an unrestricted research grant from UCB Pharma (The Netherlands). J.S. received financial support from the Spanish government (grants EUI-EURC-2011-4325 within the EuroEPINOMICS-RES network and grant SAF2010-18586). D.E.C. received an unrestricted educational grant from UCB Pharma. P.Q.T. is a Pfizer Australia Research Fellow. K.M.K. was supported by a research fellowship from the Deutsche Forschungsgemeinschaft (KL 2254/1-1) and a scholarship from The University of Melbourne. This study makes use of data generated by the DECIPHER Consortium. A full list of centers who contributed to the generation of the data is available from the consortium website and via e-mail (decipher@sanger.ac.uk). Funding for the project was provided by the Wellcome Trust.

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Author notes

  1. Leanne M Dibbens and Boukje de Vries: These authors contributed equally to this work.

Authors and Affiliations

  1. Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia

    Leanne M Dibbens, Sarah E Heron, Bree L Hodgson & Xenia Iona

  2. Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia

    Leanne M Dibbens & Sarah E Heron

  3. Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands

    Boukje de Vries, Claudia M Weller & Arn M J M van den Maagdenberg

  4. Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium

    Simona Donatello, Satyan Chintawar & Massimo Pandolfo

  5. Northern Health, Melbourne, Victoria, Australia

    Douglas E Crompton

  6. Department of Medicine, Epilepsy Research Centre, The University of Melbourne, Melbourne, Victoria, Australia

    Douglas E Crompton, Susannah T Bellows, Karl Martin Klein, Brigid M Regan, Samuel F Berkovic & Ingrid E Scheffer

  7. School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia, Australia

    James N Hughes, John C Mulley, Paul Q Thomas & Jozef Gecz

  8. Department of Neurology, Epilepsy Center Hessen, University Hospitals Giessen & Marburg, Campus Marburg, Philipps-University Marburg, Marburg, Germany

    Karl Martin Klein

  9. Department of Neurology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands

    Petra M C Callenbach & Oebele F Brouwer

  10. Neurogenetics Program, SA Pathology at Women's and Children's Hospital, Adelaide, South Australia, Australia

    Mark A Corbett & Alison E Gardner

  11. Schneider Children's Medical Center of Israel, Petach Tikvah, Israel

    Sara Kivity

  12. Central Coast Area Health Authority, Gosford, New South Wales, Australia

    Denis Crimmins

  13. Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, Victoria, Australia

    Terence J O'Brien

  14. Epilepsy Unit, Hospital Universitario Fundación Jiménez Diaz and Centro De Investigación Biomédica En Red De Enfermedades Raras (CIBERER), Madrid, Spain

    Rosa Guerrero-López & Jose Serratosa

  15. Genetic Medicine, SA Pathology at Women's and Children's Hospital, Adelaide, South Australia, Australia

    John C Mulley

  16. School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, South Australia, Australia

    John C Mulley & Jozef Gecz

  17. Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

    Francois Dubeau, Frederick Andermann & Eva Andermann

  18. IRCCS (Instituto di Ricovero e Cura a Carattere Scientifico), Istituto di Scienze Neurologiche, University of Bologna, Bologna, Italy

    Laura Licchetta & Francesca Bisulli

  19. CHUM (Centre Hospitalier de l'Université de Montréal) Research Center, University of Montreal, Montreal, Quebec, Canada

    Patrick Cossette

  20. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands

    Arn M J M van den Maagdenberg

  21. Florey Neuroscience Institute, Melbourne, Victoria, Australia

    Ingrid E Scheffer

  22. Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia

    Ingrid E Scheffer

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  1. Leanne M Dibbens
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  2. Boukje de Vries
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Contributions

L.M.D. designed and oversaw the molecular genetic aspects of the study, coordinated the study and wrote the first draft of the manuscript. B.d.V. and A.M.J.M.v.d.M. designed and carried out molecular genetics analyses and contributed to writing the manuscript. C.M.W. analyzed whole-exome sequencing data. S.E.H. analyzed molecular data, including whole-exome sequencing data. D.E.C., S.T.B., K.M.K., P.M.C.C., S.K., B.M.R., R.G.-L., D.C., T.J.O., F.D., L.L., F.B., P.C., J.S., O.F.B., F.A., E.A., M.P., S.F.B. and I.E.S. performed clinical phenotyping. B.L.H. and X.I. performed molecular studies and interpreted that data. J.C.M., A.E.G., M.A.C. and J.G. assisted with whole-exome sequencing analysis. P.Q.T. and J.N.H. performed and interpreted quantitative gene expression analyses. M.P., S.D. and S.C. performed molecular genetics analyses and designed and performed cell biology and immunohistochemistry analyses. I.E.S. and S.F.B. designed the study, oversaw the collection and clinical characterization of families and jointly wrote the manuscript. All authors contributed to the editing of the manuscript.

Corresponding authors

Correspondence to Leanne M Dibbens or Ingrid E Scheffer.

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Competing interests

I.E.S., S.F.B., L.M.D. and S.E.H. have submitted a patent application to develop a diagnostic test for DEPDC5 sequence mutations. The application was filed by ITEK Ventures Pty. Ltd. on behalf of the University of South Australia and by The University of Melbourne.

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Dibbens, L., de Vries, B., Donatello, S. et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet 45, 546–551 (2013). https://doi.org/10.1038/ng.2599

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