Abstract
The main familial focal epilepsies are autosomal dominant nocturnal frontal lobe epilepsy, familial temporal lobe epilepsy and familial focal epilepsy with variable foci. A frameshift mutation in the DEPDC5 gene (encoding DEP domain–containing protein 5) was identified in a family with focal epilepsy with variable foci by linkage analysis and exome sequencing. Subsequent pyrosequencing of DEPDC5 in a cohort of 15 additional families with focal epilepsies identified 4 nonsense mutations and 1 missense mutation. Our findings provided evidence of frequent (37%) loss-of-function mutations in DEPDC5 associated with a broad spectrum of focal epilepsies. The implication of a DEP (Dishevelled, Egl-10 and Pleckstrin) domain–containing protein that may be involved in membrane trafficking and/or G protein signaling opens new avenues for research.
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Acknowledgements
We thank the genotyping and sequencing platform of ICM for technical assistance, the DNA and cell bank of ICM for DNA extraction and cell culture, P. Couarch for technical assistance, M. Gaussen for linkage analysis and C. Depienne for helpful discussions. S.I. received a grant from the French government. This study was supported by the program Investissements d'Avenir ANR-10-IAIHU-06.
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S.I. performed experiments and analyzed data. F.P. performed phenotyping and collected clinical data. G.R. collected samples and extracted DNA. E.N. and E.M. participated in genetic experiments. G.A. carried out the bioinformatics analysis on DEPDC5 and statistical analysis. P.T., P.G., M.W., C.M. and E.H. performed phenotyping of families. R.M. and M.B. contributed to the writing of the manuscript. E.L. supervised the project and contributed to the writing of the manuscript. S.B. designed the study, supervised data analysis and wrote the manuscript.
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Ishida, S., Picard, F., Rudolf, G. et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat Genet 45, 552–555 (2013). https://doi.org/10.1038/ng.2601
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DOI: https://doi.org/10.1038/ng.2601
