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Mutations in DEPDC5 cause familial focal epilepsy with variable foci

Dibbens et al. (2013)

Nature Genetics 45: 546–551.

Mutations of DEPDC5 cause autosomal dominant focal epilepsies

Ishida et al. (2013)

Nature Genetics 45: 552–555.

Epilepsy is a chronic disorder characterized by recurrent seizures, which may vary from a brief lapse of attention or muscle jerks, to severe and prolonged convulsions. Familial focal epilepsy with variable foci (FFEVF; MIM 604364) is an autosomal dominant partial epilepsy syndrome with incomplete penetrance. Different family members have focal seizures emanating from different cortical locations that include temporal, frontal, centroparietal, or occipital lobe regions. Each individual patient has the same electro-clinical pattern of single location focal epilepsy. FFEVF is a relatively rare syndrome and the exact incidence remains unclear. However, to date at least 10 families from Australian, European, Dutch, French-Canadian, Spanish and Chinese decent have been reported [1]. Linkage studies have mapped FFEVF to a 5.3-Mb region on chromosome 22q12. In a recent issue of Nature Genetics, Dibbens et al. and Ishida et al. independently identified novel heterozygous mutations in DEPDC5 gene mapped to chromosome 22q12 and established these mutations as a common cause of familial focal epilepsies (Fig. 1). DEPDC5 encodes a protein of 1604 amino acids, the function of which is yet unknown. The protein contains a 80-amino acid Disheveled, Egl-10 and Pleckstrin (DEP) homology domain, found in proteins involved in G-protein signaling and membrane targeting.


Figure 1. (a) Schematic showing classification of different familial focal epilepsies. ADNFLE, autosomal dominant nocturnal frontal lobe epilepsy; ADEAF, autosomal dominant epilepsy with auditory features; FFEVF, familial focal epilepsy with variable foci. (b) List of causative genes identified in familial focal epilepsy, with DEPDC5 being the only novel gene identified for FFEVF.

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Using exome and Sanger sequencing Dibbens et al. identified nonsense mutations in the DEPDC5 gene residing within the 22q12 linkage interval. They included c.21C>G (p.Tyr7*) in an Australian family and c.1663C>T (p.Arg555*) in a Dutch family. Two Spanish families presented nonsense mutations c.4107G>A (p.Tyr1369*) and c.4606C>T(Gln1536*), respectively, while same deletion mutation (c.488_490delTGT; p.Phe164del) was found in three French-Canadian families. No mutations were found in an Australian family reported earlier by Klein et al. [2]. Dibbens et al. also identified pathogenic DEPDC5 mutations in 10 (12.2%) of 82 probands with focal epilepsy and no detectable structural lesions. All the mutations were absent in dbSNP135 and their in-house exome variant database (710 chromosomes). The penetrance of DEPDC5 mutations was estimated to be 66% (69/105) in the seven large families with FFEVF.

The mean age of seizure onset with these mutations was 12.5 years, with temporal and frontal lobe epilepsies being the most common. Majority of the mutations caused pre-mature truncation of the protein, suggesting haploinsufficiency as the disease mechanism. One proband had a de novo nonsense mutation (encoding p.Arg1268*), implicating DEPDC5 mutations also in sporadic focal epilepsies.

Dibbens et al. also provide preliminary data on the localization of DEPDC5 in mouse and human brain tissues. They observed low levels of murine Depdc5 transcripts by reverse transcription-polymerase chain reaction (RT-PCR) in all regions of the brain and detected its presence throughout brain development. Immunofluorescence studies suggested that Depdc5 was localized to the cytosol of the neuronal cell body and was mostly perinuclear with little or no extension into neuronal processes, while it was completely absent from astrocytes. Thus, the neuronal localization and its possible role in G-protein signaling and membrane targeting suggests that DEPDC5 might play an important role in neuronal signal transduction.

In the same issue of the journal, Ishida et al. identified a frameshift mutation in DEPDC5 gene in a large French family, for which a high-density genome wide scan mapped the FFEVF associated locus on chromosome 22q12. Exome sequencing for two subjects from this family revealed the same single-base deletion, c.1122delA in exon 16 of DEPDC5 gene, which caused a frameshift, p.Leu374Phefs*30. They further identified four nonsense mutations (encoding p.Arg239*, p.Arg328*, p.Gln372* and p.Gln1523*) and a missense mutation (p.Arg485Gln) by massive parallel pyrosequencing in 15 additional families with focal epilepsies. All these mutations segregated with the phenotype within the families (except p.Gln1523* where additional family members were not available) and none of the six DEPDC5 damaging mutations were present in dbSNP135 or the 1000 Genomes Project database or in the variants currently listed in National Heart, Lung and Blood Institute (NHLBI) exome variant server.

In their study, Ishida et al. identified that 37% (6 of the 16) families and around 20 subjects with epilepsy carried a DEPDC5 mutation. The mean age of onset in their cohort was 12.9 ± 10.9 (SD) years. They also observed low penetrance and variable expressivity and suggested that other factors like epigenetics or environmental factors could also contribute to the phenotype.

Similar to Dibbens et al., Ishida et al. also suggest that DEPDC5 haploinsufficiency was the likely cause of the disease in patients with FFEVF. Because five of six mutations introduce a pre-mature stop mutation, loss of function of DEPDC5 presumably causes the epileptic phenotype. They predict that four of six mutations (encoding p.Arg239*, p.Arg328*, p.Gln372* and p.Leu374Phefs*30 alterations) undergo nonsense mediated decay (NMD). They confirmed this by treating cultured lymphoblast encoding p.Arg239* from three mutation carriers and one spouse with an NMD inhibitor, emetine, which led to the detection of the mutation only when NMD was inhibited.

Identification of DEPDC5 as a causative mutation in 12% of pedigrees (Dibbens et al.) and 37% families (6/16; Ishida et al.) with familial focal epilepsy, suggests that DEPDC5 is a highly relevant gene to the common clinical population with non-lesional epilepsy and a positive family history. Approaches like gene knockdown and animal models could provide good insight into the function and mechanism by which mutations in DEPDC5 cause focal seizures. On the clinical front, this information would be beneficial for improving diagnosis of FFEVF by molecular testing, and in providing tailor treatments targeting DEPDC5 to improve the prognosis.


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