Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mutations in DEPDC5 cause familial focal epilepsy with variable foci

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

Accession codes

Accessions

NCBI Reference Sequence

References

  1. Scheffer, I.E. et al. Familial partial epilepsy with variable foci: a new partial epilepsy syndrome with suggestion of linkage to chromosome 2. Ann. Neurol. 44, 890–899 (1998).

    Article  CAS  Google Scholar 

  2. Xiong, L. et al. Mapping of a gene determining familial partial epilepsy with variable foci to chromosome 22q11-q12. Am. J. Hum. Genet. 65, 1698–1710 (1999).

    Article  CAS  Google Scholar 

  3. Callenbach, P.M.C. et al. Familial partial epilepsy with variable foci in a Dutch family: clinical characteristics and confirmation of linkage to chromosome 22q. Epilepsia 44, 1298–1305 (2003).

    Article  CAS  Google Scholar 

  4. Berkovic, S.F. et al. Familial partial epilepsy with variable foci: clinical features and linkage to chromosome 22q12. Epilepsia 45, 1054–1060 (2004).

    Article  Google Scholar 

  5. Klein, K.M. et al. Familial focal epilepsy with variable foci mapped to chromosome 22q12: expansion of the phenotypic spectrum. Epilepsia 53, e151–e155 (2012).

    Article  CAS  Google Scholar 

  6. Morales-Corraliza, J. et al. Familial partial epilepsy with variable foci: a new family with suggestion of linkage to chromosome 22q12. Epilepsia 51, 1910–1914 (2010).

    Article  CAS  Google Scholar 

  7. Firth, H.V. et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Am. J. Hum. Genet. 84, 524–533 (2009).

    Article  CAS  Google Scholar 

  8. Heron, S.E., Scheffer, I.E., Berkovic, S.F., Dibbens, L.M. & Mulley, J.C. Channelopathies in idiopathic epilepsy. Neurotherapeutics 4, 295–304 (2007).

    Article  CAS  Google Scholar 

  9. Heron, S.E. et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturanl frontal lobe epilepsy. Nat. Genet. 44, 1188–1190 (2012).

    Article  CAS  Google Scholar 

  10. Mulley, J.C. & Dibbens, L.M. Genetic variations and associated pathophysiology in the management of epilepsy. Appl. Clin. Genet. 4, 113–125 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen, S. & Hamm, H.E. DEP domains: more than just membrane anchors. Dev. Cell 11, 436–438 (2006).

    Article  CAS  Google Scholar 

  12. Simons, M. et al. Electrochemical cues regulate assembly of the Frizzled/Dishevelled complex at the plasma membrane during planar epithelial polarization. Nat. Cell Biol. 11, 286–294 (2009).

    Article  CAS  Google Scholar 

  13. Kharrat, A. et al. Conformational stability studies of the pleckstrin DEP domain: definition of the domain boundaries. Biochim. Biophys. Acta 1385, 157–164 (1998).

    Article  CAS  Google Scholar 

  14. Pan, W.J. et al. Characterization of function of three domains in dishevelled-1: DEP domain is responsible for membrane translocation of dishevelled-1. Cell Res. 14, 324–330 (2004).

    Article  CAS  Google Scholar 

  15. Park, M. & Shen, K. WNTs in synapse formation and neuronal circuitry. EMBO J. 31, 2697–2704 (2012).

    Article  CAS  Google Scholar 

  16. Kinton, L. et al. Partial epilepsy with pericentral spikes: a new familial epilepsy syndrome with evidence for linkage to chromosome 4p15. Ann. Neurol. 51, 740–749 (2002).

    Article  Google Scholar 

  17. Scheffer, I.E. & Berkovic, S.F. Generalized epilepsy with febrile seizures plus: a genetic disorder with heterogenous clinical phenotypes. Brain 120, 479–490 (1997).

    Article  Google Scholar 

  18. Sharp, A.J. et al. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat. Genet. 40, 322–328 (2008).

    Article  CAS  Google Scholar 

  19. Helbig, I. et al. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat. Genet. 41, 160–162 (2009).

    Article  CAS  Google Scholar 

  20. Crompton, D.E. et al. Familial mesial temporal lobe epilepsy: a benign epilepsy syndrome showing complex inheritance. Brain 133, 3221–3231 (2010).

    Article  Google Scholar 

  21. Reutens, D.C., Howell, R.A., Gebert, K.E. & Berkovic, S.F. Validation of a questionnaire for clinical seizure diagnosis. Epilepsia 33, 1065–1071 (1992).

    Article  CAS  Google Scholar 

  22. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    Article  CAS  Google Scholar 

  23. Kouadjo, K.E., Nishida, Y., Cadrin-Girard, J.F., Yoshioka, M. & St-Amand, J. Housekeeping and tissue-specific genes in mouse tissues. BMC Genomics 8, 127 (2007).

    Article  Google Scholar 

  24. Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

    Article  CAS  Google Scholar 

  25. Dottori, M. & Pera, M.F. Neural differentiation of human embryonic stem cells. Methods Mol. Biol. 438, 19–30 (2008).

    Article  CAS  Google Scholar 

  26. Witcher, M., Ross, D.T., Rousseau, C., Deluca, L. & Miller, W.H. Synergy between all-trans retinoic acid and tumor necrosis factor pathways in acute leukemia cells. Blood 102, 237–245 (2003).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

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.

Ethics declarations

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.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1 and 2 and Supplementary Figures 1–3 (PDF 4924 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2599

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing