Genetic and neurodevelopmental spectrum of<i>SYNGAP1</i>-associated intellectual disability and epilepsy

Mignot, Cyril; Stülpnagel, Celina von; Nava, Caroline; Ville, Dorothée; Sanlaville, Damien; Lesca, Gaëtan; Rastetter, Agnès; Gachet, Benoît; Marie, Yannick; Korenke, Georg Christoph; Borggraefe, Ingo; Hoffmann-Zacharska, Dorota; Szczepanik, Elżbieta; Rudzka-Dybała, Mariola; Yış, Uluç; Çağlayan, Hande; Isapof, Arnaud; Marey, Isabelle; Panagiotakaki, Eleni; Korff, Christian; Rossier, Eva; Rieß, Angelika; Beck‐Woedl, Stefanie; Rauch, Anita; Zweier, Christiane; Hoyer, Juliane; Миронов, М. Б.; Бобылова, М. Ю.; Мухин, К. Ю.; Hernández-Hernández, Laura; Maher, Bridget; Sisodiya, Sanjay M.; Kuhn, Marius; Glaeser, Dieter; Weckhuysen, Sarah; Myers, Candace T.; Mefford, Heather C; Hörtnagel, Konstanze; Biskup, Saskia; Lemke, Johannes R.; Héron, Delphine; Kluger, Gerhard; Depienne, Christel

doi:10.1136/jmedgenet-2015-103451

Cited by 138 publications

(205 citation statements)

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“…In humans, photosensitivity is an age-dependent phenomenon and is more prevalent in children with a peak age of onset about 12 y (27). There is also strong evidence for a genetic component of photoparoxysmal response (PPR) in humans and many loci have been identified (27)(28)(29)(30). Thus, affected RRs provide another spontaneous large animal model to investigate the neural mechanisms of photosensitivity (31,32).…”

Section: Discussionmentioning

confidence: 99%

Generalized myoclonic epilepsy with photosensitivity in juvenile dogs caused by a defective DIRAS family GTPase 1

Wielaender

Sarviaho

James

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The clinical and electroencephalographic features of a canine generalized myoclonic epilepsy with photosensitivity and onset in young Rhodesian Ridgeback dogs (6 wk to 18 mo) are described. A fully penetrant recessive 4-bp deletion was identified in the DIRAS family GTPase 1 (DIRAS1) gene with an altered expression pattern of DIRAS1 protein in the affected brain. This neuronal DIRAS1 gene with a proposed role in cholinergic transmission provides not only a candidate for human myoclonic epilepsy but also insights into the disease etiology, while establishing a spontaneous model for future intervention studies and functional characterization.seizure | juvenile | canine | photosensitivity | Ras

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Section: Discussionmentioning

confidence: 99%

Generalized myoclonic epilepsy with photosensitivity in juvenile dogs caused by a defective DIRAS family GTPase 1

Wielaender

Sarviaho

James

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Pathogenic Syngap1 variants cause a genetically defined form of intellectual disability [19] with epilepsy [20], termed MRD5, that accounts for up to 0.5-1% of severe childhood brain disorders [21,22]. This disorder is caused by de novo SYNGAP1 mutations that induce genetic haploinsufficiency [23,24]. Probes that increase Syngap1 expression in neurons would target the root cause of MRD5.…”

Section: Resultsmentioning

confidence: 99%

Improved Scalability of Neuron-Based Phenotypic Screening Assays for Therapeutic Discovery in Neuropsychiatric Disorders

et al. 2017

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There is a pressing need to improve approaches for drug discovery related to neuropsychiatric disorders (NSDs). Therapeutic discovery in neuropsychiatric disorders would benefit from screening assays that can measure changes in complex phenotypes linked to disease mechanisms. However, traditional assays that track complex neuronal phenotypes, such as neuronal connectivity, exhibit poor scalability and are not compatible with high-throughput screening (HTS) procedures. Therefore, we created a neuronal phenotypic assay platform that focused on improving the scalability and affordability of neuron-based assays capable of tracking disease-relevant phenotypes. First, using inexpensive laboratory-level automation, we industrialized primary neuronal culture production, which enabled the creation of scalable assays within functioning neural networks. We then developed a panel of phenotypic assays based on culturing of primary neurons from genetically modified mice expressing HTS-compatible reporters that capture disease-relevant phenotypes. We demonstrated that a library of 1,280 compounds was quickly screened against both assays using only a few litters of mice in a typical academic laboratory setting. Finally, we implemented one assay in a fully automated high-throughput academic screening facility, illustrating the scalability of assays designed using this platform. These methodological improvements simplify the creation of highly scalable neuron-based phenotypic assays designed to improve drug discovery in CNS disorders.

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“…Now, it is admitted that some psychiatric disorders share common genetic bases with epilepsy [7]. Indeed, genetic studies of copy number variants (CNVs) have shown that in some cases, the same CNV is identified in PWE and in individuals with other neuropsychiatric conditions such as autism spectrum disorders, schizophrenia, mental retardation and attention deficit hyperactivity disorders [8].…”

Section: What Are the Mechanisms Underlying These Disorders?mentioning

confidence: 99%

Epilepsy and Psychiatric Disorders: Is There a Common Genetic Susceptibility?

Chentouf¹

2016

J Epilepsy

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Genetic and neurodevelopmental spectrum ofSYNGAP1-associated intellectual disability and epilepsy

Cited by 138 publications

References 40 publications

Generalized myoclonic epilepsy with photosensitivity in juvenile dogs caused by a defective DIRAS family GTPase 1

Generalized myoclonic epilepsy with photosensitivity in juvenile dogs caused by a defective DIRAS family GTPase 1

Improved Scalability of Neuron-Based Phenotypic Screening Assays for Therapeutic Discovery in Neuropsychiatric Disorders

Epilepsy and Psychiatric Disorders: Is There a Common Genetic Susceptibility?

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