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Mutations of DEPDC5 Cause Autosomal Dominant Focal Epilepsies

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Mutations of DEPDC5 Cause Autosomal Dominant Focal Epilepsies LETTERS Mutations of DEPDC5 cause autosomal dominant focal epilepsies Saeko Ishida1,2, Fabienne Picard3, Gabrielle Rudolf4,5, Eric Noé1,2, Guillaume Achaz2,6,7, Pierre Thomas8, Pierre Genton9,10, Emeline Mundwiller11, Markus Wolff12, Christian Marescaux4, Richard Miles1,2, Michel Baulac1,2,13, Edouard Hirsch4, Eric Leguern1,2,14 & Stéphanie Baulac1,2 The main familial focal epilepsies are autosomal dominant yet been identified for FFEVF, linkage to 22q12 has been reported in nocturnal frontal lobe epilepsy, familial temporal lobe several families4,8–11. epilepsy and familial focal epilepsy with variable foci. We have previously described the electroclinical characteristics of A frameshift mutation in the DEPDC5 gene (encoding DEP 19 families with autosomal dominant focal epilepsies, subdivided into domain–containing protein 5) was identified in a family with ADNFLE, FTLE and FFEVF12. Two large multiplex French families (N focal epilepsy with variable foci by linkage analysis and exome and S) with diagnosed FFEVF were selected from this cohort for link- sequencing. Subsequent pyrosequencing of DEPDC5 in a age analysis using a high-density genome-wide scan with 10,000 SNPs. All rights reserved. cohort of 15 additional families with focal epilepsies Both families mapped to the FFEVF-associated locus on chromosome identified 4 nonsense mutations and 1 missense mutation. 22q12, with maximum logarithm of odds (LOD) scores of 2.08 (fam- Our findings provided evidence of frequent (37%) loss-of- ily N) and 1.81 (family S). Haplotype reconstruction confirmed the function mutations in DEPDC5 associated with a broad segregation of a disease haplotype in both families (Supplementary spectrum of focal epilepsies. The implication of a DEP Figs. 1 and 2). America, Inc. (Dishevelled, Egl-10 and Pleckstrin) domain–containing We then sequenced the entire exome of subjects N-III:4 and protein that may be involved in membrane trafficking and/or N-III:6 and sought rare coding variants in the 22q12 candidate G protein signaling opens new avenues for research. region. In both individuals, we found the same single-base deletion, c.1122delA, in exon 16 of the DEPDC5 gene (also known as KIAA0645; Epilepsy is a frequent neurological disorder characterized by sponta- NM_001242896). This variant caused a frameshift, p.Leu374Phefs*30, © 2013 Nature neous, recurrent seizures. Focal epileptic seizures are thought to origi- introducing a premature stop codon 29 amino acids downstream. nate within networks limited to one hemisphere. Several autosomal The c.1122delA variant fully segregated with the phenotype within dominant, non-lesional focal epilepsies have been described as spe- the family (Fig. 1). npg cific age-related and electroclinical syndromes: autosomal dominant We next sought DEPDC5 mutations in 15 additional probands from nocturnal frontal lobe epilepsy (ADNFLE; MIM 600513)1, familial the families with autosomal dominant focal epilepsies (ADNFLE, temporal lobe epilepsy (FTLE; MIM 600512)2, including mesial and n = 7; FTLE, n = 4; FFEVF, n = 4)12, including family S in which lateral forms (also termed autosomal dominant epilepsy with auditory disease was linked to the 22q12 locus. Massively parallel pyrose- features (ADEAF; MIM 604619)3, and familial focal epilepsy with quencing screening of all 43 exons and splice regions of DEPDC5 variable foci (FFEVF; MIM 604364), characterized by focal seizures identified 4 further nonsense mutations (encoding p.Arg239* in that are initiated in distinct cortical regions in different family mem- family S, p.Arg328* in family L, p.Gln372* in family Q and p.Gln1523* bers4. The only gene mutations currently identified are those linked in family B) and 1 missense mutation (p.Arg485Gln in family O) in to ADNFLE (CHRNA4, CHRNA2, CHRNB2 and KCNT1, encoding, 5 families (Fig. 2a, Table 1 and Supplementary Fig. 3). All muta- respectively, the α4, α2 and β2 subunits of the neuronal nicotinic tions were shown to segregate with the phenotype within the families, acetylcholine receptor and a potassium channel subunit)5,6 and to except for the mutation encoding p.Gln1523* in family B, where addi- ADEAF (LGI1, encoding epitempin)7. Although no causal genes have tional family members were unavailable for analysis (Fig. 1). In family 1Institut National de la Santé et de la Recherche Médicale (INSERM) U975, Institut du Cerveau et de la Moelle Epinière (ICM), Hôpital Pitié-Salpêtrière, Paris, France. 2Université Pierre et Marie Curie–Paris 6 (UPMC), Paris, France. 3Department of Neurology, University Hospitals of Geneva (HUG), Geneva, Switzerland. 4Neurology Department, Strasbourg University Hospital, Strasbourg, France. 5Strasbourg University (UDS), Strasbourg, France. 6Unité Mixte de Recherche (UMR) 7138, Centre National de la Recherche Scientifique (CNRS), Paris, France. 7UMR 7241, Collège de France, Paris, France. 8Service de Neurologie, Hôpital Pasteur, Nice, France. 9Centre Saint Paul, Henri Gastaut, Marseille, France. 10Mediterranean Institute of Neurobiology (INMED), Marseille, France. 11Genotyping/Sequencing Platform of ICM, Hôpital Pitié-Salpêtrière, Paris, France. 12Department of Pediatric Neurology, University Children’s Hospital, Tuebingen, Germany. 13Epilepsy Unit, Assistance Publique–Hôpitaux de Paris (AP-HP) Groupe Hospitalier Pitié-Salpêtrière, Paris, France. 14Département de Génétique et de Cytogénétique, AP-HP Groupe Hospitalier Pitié-Salpêtrière, Paris, France. Correspondence should be addressed to S.B. ([email protected]). Received 21 December 2012; accepted 7 March 2013; published online 31 March 2013; doi:10.1038/ng.2601 552 VOLUME 45 | NUMBER 5 | MAY 2013 NATURE GENETICS LETTERS Family N: c.1122delA Family L: c.982C>T Database of Genomic Variants. DEPDC5 I mutations occurred significantly more often I 1 2 1 2 in our group of affected individuals (5/32; +/+ m/+ P = 5 × 10−12, Fisher exact test). II II Four out of six mutations (encod- 2 3 7 1 6 5 4 8 2 1 m/+ +/+ +/+ +/+ m/+ +/+ m/+ ing p.Arg239*, p.Arg328*, p.Gln372* and p.Leu374Phefs*30 alterations) are predicted III III 1 2 3 4 9 5 6 10 7 8 1 2 to result in degradation of the mutated tran- +/+ +/+ m/+ m/+ m/+ m/+ +/+ m/+ +/+ m/+ m/+ script by the nonsense-mediated mRNA IV decay (NMD) system, whereas the nonsense Family Q: c.1114C>T 1 2 3 4 5 6 7 mutation encoding p.Gln1523*, located in +/+ m/+ m/+ +/+ m/+ I the last exon of the gene, is not likely to be 1 2 targeted by the NMD system. To confirm Family S: c.715C>T +/+ m/+ that the mutation encoding the p.Arg239* II I ?? alteration leads to NMD, we treated cultured 1 4 2 3 5 1 2 m/+ lymphoblasts from three mutation carriers III II (S-III:10, S-IV:7 and S-IV:9) and one spouse 1 1 2 3 4 5 6 (S-III:11) with emetine, an NMD inhibi- Family B: c.4567C>T tor. With sequencing of DEPDC5 cDNA III 2 2 I the mutation encoding p.Arg239* was only 4 5 3 7 6 10 11 12 13 14 15 18 16 17 1 2 m/+ +/+ m/+ +/+ +/+ m/+ m/+ detected when NMD was inhibited (Fig. 2c), II showing that this nonsense mutation speci- IV 3 2 1 4 fically leads to transcript degradation. 12 3 4 5 6 10 78 9 12 11 +/+ m/+ m/+ m/+ m/+ DEPDC5 haploinsufficiency is likely to be III 1 2 3 4 the cause of disease in individuals carrying V this mutation. 6 1 2 3 4 5 All rights reserved. m/+ m/+ m/+ m/+ IV We identified mutations in one-third of 1 2 3 the families in our cohort (6/16, 37%), and, m/+ overall, 20 subjects with epilepsy carried a Family O: c.1454G>A Focal epilepsy DEPDC5 mutation. The age of disease onset I Generalized epilepsy ranged from 0 to 39 years (mean of 12.9 ± America, Inc. 1 2 3 4 5 10.9 (s.d.)). DEPDC5 mutations were not lim- Lesional focal epilepsy ited to families with the FFEVF phenotype II Electrical seizure but were also found in a family with two indi- 12 3 5 4 6 7 8 9 10 11 12 +/+ Undefined epilepsy viduals exhibiting a typical nocturnal fron- 13 m Mutated tal lobe epilepsy (family B) and two other III © 2013 Nature 12 3 4 5 6 7 8 9 10 11 12 + Not mutated families (L and O) with individuals with tem- m/+ m/+ poral lobe seizures. A phenotype of FFEVF Figure 1 Pedigrees of families with segregation of DEPDC5 mutations. Identified DEPDC5 was attributed to family N because frontal npg mutations included c.1122delA (p.Leu374Phefs*30) in family N, c.715C>T (p.Arg239*) seizures have been diagnosed in one fam- in family S, c.982C>T (p.Arg328*) in family L, c.1114C>T (p.Gln372*) in family Q, c.1454G>A ily member (N-IV:5), and frontal electrical (p.Arg485Gln) in family O and c.4567C>T (p.Gln1523*) in family B. Individual N-IV:4 showed seizures were identified in another (N-IV:4), frontal spikes in electroencephalography (EEG) but no clinical seizure. A question mark whereas seizures in other family members indicates individuals born in the 1870s with doubtful epilepsy histories. Diagonal lines indicate deceased individuals. originate in the temporal lobe. Penetrance was incomplete in families N, S and O, in agreement with reports of low penetrance of O, the father (O-II:8) may have transmitted the mutation encod- 62% (ref. 14) or 50% (ref. 4) in families with FFEVF. Seven asympto- ing p.Arg485Gln, as it was not inherited from the mother (O-II:7). matic obligate carriers (N-II:2, S-II:5, S-III:4, S-III:7, S-III:10, S-IV:5 The arginine at position 485 is a highly conserved amino acid (Fig. 2b). and O-II:8) and four asymptomatic at-risk individuals aged 8–42 years Different prediction software tools—MutationTaster, SIFT and (N-III:5, N-IV:7, S-IV:7 and S-V:2) carried the mutations.
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