De Novo SYNGAP1 Mutations in Nonsyndromic Intellectual Disability and Autism

Hamdan, Fadi F.; Daoud, Hussein; Piton, Amélie; Gauthier, Julie; Dobrzeniecka, Sylvia; Krebs, Marie‐Odile; Joober, Ridha; Lacaille, Jean‐Claude; Nadeau, Amélie; Milunsky, Jeff M.; Wang, Zhenyuan; Carmant, Lionel; Mottron, Laurent; Beauchamp, Miriam H.; Rouleau, Guy A.; Michaud, Jacques L.

doi:10.1016/j.biopsych.2010.11.015

Cited by 175 publications

(133 citation statements)

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“…Supplementary Table I summarizes the available clinical data on the 26 individuals who have been reported to date with presumed causative mutations in SYNGAP1 or deletions or translocations involving this gene [Hamdan et al, 2009, 2011a, b; Krepischi et al, 2010; Pinto et al, 2010; Vissers et al, 2010; Cook, 2011; Klitten et al, 2011; Zollino et al, 2011; Clement et al, 2012; de Ligt et al, 2012; Rauch et al, 2012; Berryer et al, 2013; Carvill et al, 2013; Writzl and Knegt, 2013; Dyment et al, 2014; O'Roak et al, 2014; Redin et al, 2014]. De novo mutations in this gene are undoubtedly a significant cause of intellectual disability, accounting for 0.62% of all the patients in the DDD Study [Wright et al, 2014] and major contributors to other cohorts that have been studied (Supplementary Table II).…”

Section: Discussionmentioning

confidence: 99%

“…Heterozygous, de novo loss‐of‐function mutations in SYNGAP1 have been described in 26 individuals to date [Hamdan et al, 2009, 2011a, b; Krepischi et al, 2010; Pinto et al, 2010; Vissers et al, 2010; Zollino et al, 2011; de Ligt et al, 2012; Rauch et al, 2012; Berryer et al, 2013; Carvill et al, 2013; Writzl and Knegt, 2013; Redin et al, 2014]. SYNGAP1 encodes Ras/Rap GTPase‐activating protein SynGAP, which is a major component of the post‐synaptic density that regulates synaptic plasticity and ERK/MAPK signaling probably via N‐methyl‐d‐aspartate (NMDA) receptor activation [Komiyama et al, 2002; Muhia et al, 2010].…”

Section: Introductionmentioning

confidence: 99%

“…This group subsequently published eight further affected individuals through re‐sequencing predominantly ID cohorts enriched for epilepsy [2011a, b; Berryer et al, 2013]. Carvill et al performed massively parallel sequencing in 500 individuals with epileptic encephalopathy and identified four patients with de novo SYNGAP1 mutations [Carvill et al, 2013].…”

Section: Introductionmentioning

confidence: 99%

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De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

Parker

Fryer

Shears

et al. 2015

American J of Med Genetics Pt A

109

115

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De novo mutations (DNM) in SYNGAP1, encoding Ras/Rap GTPase‐activating protein SynGAP, have been reported in individuals with nonsyndromic intellectual disability (ID). We identified 10 previously unreported individuals with SYNGAP1 DNM; seven via the Deciphering Developmental Disorders (DDD) Study, one through clinical analysis for copy number variation and the remaining two (monozygotic twins) via a research multi‐gene panel analysis. Seven of the nine heterozygous mutations are likely to result in loss‐of‐function (3 nonsense; 3 frameshift; 1 whole gene deletion). The remaining two mutations, one of which affected the monozygotic twins, were missense variants. Each individual carrying a DNM in SYNGAP1 had moderate‐to‐severe ID and 7/10 had epilepsy; typically myoclonic seizures, absences or drop attacks. 8/10 had hypotonia, 5/10 had significant constipation, 7/10 had wide‐based/unsteady gait, 3/10 had strabismus, and 2/10 had significant hip dysplasia. A proportion of the affected individuals had a similar, myopathic facial appearance, with broad nasal bridge, relatively long nose and full lower lip vermilion. A distinctive behavioral phenotype was also observed with aggressive/challenging behavior and significant sleep problems being common. 7/10 individuals had MR imaging of the brain each of which was reported as normal. The clinical features of the individuals reported here show significant overlap with those associated with 6p21.3 microdeletions, confirming that haploinsufficiency for SYNGAP1 is responsible for both disorders. © 2015 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

Parker

Fryer

Shears

et al. 2015

American J of Med Genetics Pt A

109

115

View full text Add to dashboard Cite

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“…Because reducing SynGAP1 levels in neurons has been shown previously to stabilize the actin network in spines, leading to activity-independent spine stability (59), our data suggest that layer I spine stabilization as a result of sensory deprivation could be caused, in part, by reduced SynGAP1 protein levels in this region and that these layer I synapses could be stabilized independent of activity levels. Therefore, in addition to its wellcharacterized role in cognition (83,84), SynGAP1 appears to play a prominent role in experience-dependent plasticity. Furthermore, the reduction of SynGAP1 in the spines of layer I suggest that SynGAP1 may be an attractive candidate for future in vivo optical imaging studies of somatosensory plasticity.…”

Section: Discussionmentioning

confidence: 99%

In vivo quantitative proteomics of somatosensory cortical synapses shows which protein levels are modulated by sensory deprivation

Butko¹,

Savas

Friedman³

et al. 2013

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

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Postnatal bilateral whisker trimming was used as a model system to test how synaptic proteomes are altered in barrel cortex by sensory deprivation during synaptogenesis. Using quantitative mass spectrometry, we quantified more than 7,000 synaptic proteins and identified 89 significantly reduced and 161 significantly elevated proteins in sensory-deprived synapses, 22 of which were validated by immunoblotting. More than 95% of quantified proteins, including abundant synaptic proteins such as PSD-95 and gephyrin, exhibited no significant difference under high-and low-activity rearing conditions, suggesting no tissue-wide changes in excitatory or inhibitory synaptic density. In contrast, several proteins that promote mature spine morphology and synaptic strength, such as excitatory glutamate receptors and known accessory factors, were reduced significantly in deprived synapses. Immunohistochemistry revealed that the reduction in SynGAP1, a postsynaptic scaffolding protein, was restricted largely to layer I of barrel cortex in sensorydeprived rats. In addition, protein-degradation machinery such as proteasome subunits, E2 ligases, and E3 ligases, accumulated significantly in deprived synapses, suggesting targeted synaptic protein degradation under sensory deprivation. Importantly, this screen identified synaptic proteins whose levels were affected by sensory deprivation but whose synaptic roles have not yet been characterized in mammalian neurons. These data demonstrate the feasibility of defining synaptic proteomes under different sensory rearing conditions and could be applied to elucidate further molecular mechanisms of sensory development. mass spectrometric proteomics | somatosensory cortex | experience-dependent plasticity | synaptic protein dynamics S ensory information is encoded in the brain by activation of specific neuronal circuits that operate via chemical synapses. Important sensory experiences are stored by strengthening activated synapses in the circuit, a process known as "experience-dependent plasticity" (1). When animals are deprived of sensory experience during development, for example, by trimming rodent whiskers from birth to 30 d after birth, synaptic strength and mature synaptic morphology are attenuated, suggesting that the low activity in the deprived circuits interferes with normal development (2-7). However, the molecular changes that alter these synaptic properties in response to experience remain unclear. Synaptic activation has been shown to promote regulated and highly localized effects on synaptic proteins such as local translation, recruitment, and targeted degradation (8-11), and this spatiotemporal control of protein availability is required for long-term plasticity and synaptic maturation, which are fundamental in memory formation and storage and ultimately for an organism's survival (12-14). The need for highly controlled protein availability is highlighted in studies of neurological diseases, which often result from the disruption of protein availability at the synapse (15-17). ...

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“…In mice, SynGAP1 accelerates the maturation of dendritic spines leading to disruptions in synaptic transmission and cognitive function [307][308][309][310] . Several de novo mutations of SYNGAP1 have also been associated with ASD 43,64,306,[311][312][313][314][315] . Together these results…”

Section: Accepted Manuscriptmentioning

confidence: 99%