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DEPDC5 Takes a Second Hit in Familial Focal Epilepsy

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DEPDC5 Takes a Second Hit in Familial Focal Epilepsy DEPDC5 takes a second hit in familial focal epilepsy Matthew P. Anderson J Clin Invest. 2018;128(6):2194-2196. https://doi.org/10.1172/JCI121052. Commentary Loss-of-function mutations in a single allele of the gene encoding DEP domain–containing 5 protein (DEPDC5) are commonly linked to familial focal epilepsy with variable foci; however, a subset of patients presents with focal cortical dysplasia that is proposed to result from a second-hit somatic mutation. In this issue of the JCI, Ribierre and colleagues provide several lines of evidence to support second-hit DEPDC5 mutations in this disorder. Moreover, the authors use in vivo, in utero electroporation combined with CRISPR-Cas9 technology to generate a murine model of the disease that recapitulates human manifestations, including cortical dysplasia–like changes, focal seizures, and sudden unexpected death. This study provides important insights into familial focal epilepsy and provides a preclinical model for evaluating potential therapies. Find the latest version: https://jci.me/121052/pdf COMMENTARY The Journal of Clinical Investigation DEPDC5 takes a second hit in familial focal epilepsy Matthew P. Anderson Departments of Neurology and Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. Boston Children’s Hospital Intellectual and Developmental Disabilities Research Center, Boston, Massachusetts, USA. Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA. These detailed genetic and biochemical correlations in the human tissues then led Loss-of-function mutations in a single allele of the gene encoding DEP them to design tests of causality in a mouse domain–containing 5 protein (DEPDC5) are commonly linked to familial model, in which they reconstituted many focal epilepsy with variable foci; however, a subset of patients presents with features of the human disorder. Together, focal cortical dysplasia that is proposed to result from a second-hit somatic the results of Ribierre et al. provide com- mutation. In this issue of the JCI, Ribierre and colleagues provide several pelling evidence to support the conclusion lines of evidence to support second-hit DEPDC5 mutations in this disorder. that focal epilepsy arising from DEPDC5 Moreover, the authors use in vivo, in utero electroporation combined with heterozygous mutations occurs through a CRISPR-Cas9 technology to generate a murine model of the disease that second-hit loss of function of the second recapitulates human manifestations, including cortical dysplasia–like allele, as occurs in tuberous sclerosis. changes, focal seizures, and sudden unexpected death. This study provides The mouse model developed by Rib- important insights into familial focal epilepsy and provides a preclinical ierre and colleagues allowed for further model for evaluating potential therapies. investigation into the cellular and molec- ular mechanisms of DEPDC5 mutation– driven focal epilepsy (7). The authors used an elegant approach of in vivo, in utero electroporation to deliver a CRISPR-Cas9 Familial focal epilepsy with of cortical dysplasia, as has been found vector that allowed targeted homozygous variable foci for cortical tubers that result from muta- deletions of Depdc5 alleles in cortical neu- When first described, autosomal domi- tions of the tuberous sclerosis (TSC) gene. ronal progenitor cells of the subventricular nant familial focal epilepsy with variable Like the DEPDC5-containing GATOR1 zone of fetal mouse brains. This targeted foci (FFEVF) was initially puzzling, as complex, the TSC complex (TSC1/2) also deletion led to deficits in neuronal migra- family members with this disorder had inhibits mTORC1. A second-hit somatic tion, which were rescued by the treatment seizures originating from different cortical mutation in TSC1/2 in cortical neuron pro- of pregnant dams with the mTORC1 inhib- regions (1). This presentation is unlike oth- genitors explains the variable sites of cor- itor rapamycin. Moreover, neurons with er genetic partial epilepsy disorders, such tical dysplasia that generate seizure foci as homozygous Depdc5 inactivation had ele- as autosomal dominant lateral temporal in tuberous sclerosis. vated levels of phosphorylated S6, which lobe epilepsy (ADLTE), which arises from is indicative of mTORC1 activation, and leucine-rich glioma-inactivated 1 (LGI1) DEPDC5 takes a second hit increased soma size. These observations in mutations, which are characterized by sei- in focal seizures the murine neurons recapitulated the find- zures with symptoms (auditory auras in In this issue, Ribierre et al. (7) present a ings in the human seizure resections (Fig- ADLTE) suggestive of more limited seizure tour-de-force study that provides strong ure 1). Importantly, mice with focal cortical initiation sites. Subsequently, mutations of evidence for a germline and second allele mosaic homozygous deletions of Depdc5 DEP domain–containing 5 (DEPDC5) were somatic hit (nonsense loss-of-function suffered seizures, recorded by EEG, with shown to underlie FFEVF (2, 3); however, mutation) of DEPDC5 in familial focal tonic-clonic posturing in some cases and the molecular mechanisms responsible epilepsies with focal cortical dysplasia. sometimes ending in seizure-related for the variable foci were unclear. Subse- The authors evaluated cortical resection spontaneous death (a potential focal quently, it was determined that in a subset specimens from DEPDC5 heterozygous seizure–induced sudden death in epilepsy of patients, the seizure foci contains areas subjects with focal epilepsy. In addition [SUDEP] model). of cortical dysplasia (4, 5). As DEPDC5 is to the genetics, mTORC1 signaling was part of the GATOR1 complex, which neg- hyperactive, as evidenced by increased Conclusions atively regulates mammalian target of neuronal soma size and elevated phos- The evidence that pathogenic somatic rapamycin complex 1 (mTORC1) (6), the phorylated S6 in the dysplastic neurons of mutagenesis is a cause of neurologic dis- stage was set for a second-hit mechanism the human seizure resection specimens. orders is rapidly growing. Many genes involved in the mTOR and related signal- Related Article: p. 2452 ing pathways have now been identified in focal and hemimegalencephaly cortical Conflict of interest: The author has declared that no conflict of interest exists. dysplasia cases (8–12). For many of the Reference information: J Clin Invest. 2018;128(6):2194–2196. https://doi.org/10.1172/JCI121052. identified genes, it remains unclear exactly 2194 jci.org Volume 128 Number 6 June 2018 The Journal of Clinical Investigation COMMENTARY Acknowledgments MPA receives funding from the Nation- al Institute of Neurological Disorders and Stroke (NINDS) (1R01NS08916); the National Institute of Mental Health (1R01MH114858; 1R01MH112714); the Nancy Lurie Marks Family Foundation; the Landreth Foundation; Autism Speaks/ National Alliance for Autism Research; and the Simons Foundation. Support is also provided to the Neurobiology Depart- ment of Harvard Medical School (in part through the NINDS P30 Core Center grant NS07203) and to the Boston Children’s Hospital Intellectual and Developmen- tal Disabilities Research Center (IDDRC) (1U54HD090255 and P30HD18655). Address correspondence to: Matthew P. Anderson, Center for Life Science, 330 Brookline Ave, E/CLS-645, Boston, Massachusetts 02215, USA. Phone: 617. 735.3202; Email: Matthew_Anderson@ bidmc.harvard.edu. 1. Scheffer IE, et al. Familial partial epilepsy with variable foci: a new partial epilepsy syndrome with suggestion of linkage to chromosome 2. Figure 1. Second-hit DEPDC5 mutation underlies focal cortical dysplasia in familial epilepsy. In this Ann Neurol. 1998;44(6):890–899. issue, Ribierre et al. reveal a mosaic pattern of secondary somatic mutations in DEPDC5 in cortical 2. Dibbens LM, et al. Mutations in DEPDC5 cause –/+ –/– neurons of DEPDC5 patients with focal epilepsy. The introduction of mosaic Depdc5 mutations familial focal epilepsy with variable foci. Nat in a murine model recapitulates the patient phenotype, including magnified mTOR signaling, focal Genet. 2013;45(5):546–551. seizures, and SUDEP in some cases. 3. Ishida S, et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat Genet. 2013;45(5):552–555. 4. Scheffer IE, et al. Mutations in mammalian tar- how these defects lead to epileptiform dis- evidence of somatic mutations of SCN1A get of rapamycin regulator DEPDC5 cause focal charge of the affected neuronal circuits to and other genes in autism-epilepsy comor- epilepsy with brain malformations. Ann Neurol. produce the seizure foci; however, defects bidity disorders (17, 18). These preliminary 2014;75(5):782–787. in cortical neuron migration, neuronal results suggest the possibility that genes 5. Baulac S, et al. Familial focal epilepsy with focal dendritic and axonal arbor overgrowth, involved in neurophysiologic functions that cortical dysplasia due to DEPDC5 mutations. Ann Neurol. 2015;77(4):675–683. and possibly alteration of the intrinsic would not produce a visible lesion might 6. Bar-Peled L, et al. A Tumor suppressor complex excitability of the neurons carrying these also underlie some seizure foci. with GAP activity for the Rag GTPases that sig- mutations may alter the discharge of these Considering the now well-established nal amino acid sufficiency to mTORC1. Science. dysplastic neuronal circuits. Interestingly, evidence that somatic mutations in neu- 2013;340(6136):1100–1106. activation of the mTOR signaling pathway, ronal precursor
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