Mutations of DEPDC5 cause autosomal dominant focal epilepsies

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.

Figure 1

Pedigrees of families with segregation of DEPDC5 mutations: c.1122delA (p.Leu374Phefs*30) in family N, c.715C>T (p.Arg239*) in family S, c.982C>T (p.Arg328*) in family L, c.1114C>T (p.Gln372*) in family Q, c.1454G>A (p.Arg485Gln) in family O, c.4567C>T (p.Gln1523*) in family B. Individual N-IV:4 showed frontal spikes at the EEG, but no clinical seizure; ? indicates individuals born in the 1870s, with doubtful epilepsy histories. Diagonal lines indicate deceased individuals.

Figure 2

(a) Illustration of the exon-intron structure of DEPDC5 gene with the position of the mutations based on the human genomic sequence (RefSeq NM_001242896) and protein. DEPDC5 is a multidomain protein carrying an N-terminal domain of unknown function termed DUF3608 and a DEP domain at the C-terminal. Mutations p.Arg239*, p.Arg328*, p.Gln372*, p.Leu374Phefs*30 are clustered in the DUF3608 domain. (b) Multiple protein alignment showing conservation of the arginine residue in position 485 in orthologs of DEPDC5 across species. (c) Sequence chromatograms of one affected (S-IV:9) and one unaffected (S-III:11) member of family S, showing the presence of p.Arg239* mutation in DEPDC5 cDNA of S-IV:9 lymphoblasts pretreated with emetine, but not in untreated cells.