SYNGAP1 mutations: Clinical, genetic, and pathophysiological features

Abstract

SYNGAP1 is a gene that encodes the cytosolic protein SYNGAP1 (SYNaptic GTPase Activating Protein), an essential component of the postsynaptic density at excitatory glutamatergic neurons. SYNGAP1 plays critical roles in synaptic development, structure, function, and plasticity. Mutations in SYNGAP1 result in a neurodevelopmental disorder termed Mental retardation‐type 5 (MRD5, OMIM #612621) with a phenotype consisting of intellectual disability, motor impairments, and epilepsy, attesting to the importance of this protein for normal brain development. Here we review the clinical and pathophysiological aspects of SYNGAP1 mutations with a focus on their effect on synaptogenesis, neural circuit function, and cellular plasticity. We conclude by comparing the molecular pathogenesis of SYNGAP1 mutations with those of another neurodevelopmental disorder that affects dendritic function and cellular plasticity, fragile X syndrome. Insights into the molecular similarities and differences underlying these disorders could lead to rationale therapy development.

Twenty Years of SynGAP Research: From Synapses to Cognition

“…It is estimated that these SYNGAP1 mutations may account for up to 1% of all cases of nonsyndromic ID (Hamdan et al, 2009). However, with an increase in the number of identified patients harboring SYNGAP1 mutations, it is now apparent that SYNGAP1 loss-of-function mutations precipitate a constellation of symptoms that can be classified as a single disorder, Mental retardation, autosomal dominant 5 (MRD5) (Parker et al, 2015;Agarwal et al, 2019;Holder et al, 2019). ID-causing SYNGAP1 mutations have been identified along the entire length of the SYNGAP1 gene, with most of the mutations occurring from exons 3-17 (Vlaskamp et al, 2019) (Fig.…”

“…While all patients with SYNGAP1 loss-of-function mutations exhibit some form of ID, ϳ50% are codiagnosed with ASD (Berryer et al, 2013;Parker et al, 2015;Mignot et al, 2016;Agarwal et al, 2019;Holder et al, 2019), which has long been linked to synaptic pathophysiology and is often caused by mutations in genes encoding synaptic proteins (Hamdan et al, 2011;Penzes et al, 2011;Berryer et al, 2013;O'Roak et al, 2014;Kilinc et al, 2018). Because of the increasing knowledge linking postsynaptic proteins to learning and memory, single postsynaptic proteins have garnered much attention as potential contributors to ASD etiology.…”

SynGAP splice variants display heterogeneous spatio‐temporal expression and subcellular distribution in the developing mammalian brain

“…Thus, the multitude of available N-and C-termini likely bestows distinctive functional properties to SynGAP isoforms. However, the expression pattern and subcellular localization of distinct SynGAP isoforms remain largely unexplored, particularly during early 097037-B-100, IEDI-2017-00822 and BES-2013-063720; Career Integration Grant, Grant/Award Number: 304111; Ramón y Cajal Fellowship, Grant/Award Number: RYC-2011-08391p; AGAUR, Grant/ Award Number: SGR14-297 and 2017SGR1776; NIH, Grant/Award Number: MH096847, MH108408, NS064079 and RO1 MH112151 K E Y W O R D S pleiotropy, postnatal development, protein expression pattern, protein isoforms, subcellular localization, SynGAP postnatal development, when SynGAP is known to have a strong impact on synaptic (Clement et al, 2012(Clement et al, , 2013 or dendritic (Aceti et al, 2014;Michaelson et al, 2018) maturation and neuronal development (Muhia, Yee, Feldon, Markopoulos, & Knuesel, 2010;Agarwal et al, 2019). Here, we present a systematic study of the expression of SynGAP isoforms in five different brain regions and four postnatal developmental stages, identifying specific expression patterns for all isoforms, both between brain regions and throughout development.…”

“…De novo mutations in the human SYNGAP1 gene resulting in genetic haploinsufficiency cause mental retardation type 5 (MRD‐5; OMIM #612621), an autosomal dominant form of intellectual disability (ID) with high rates of progressively worsening childhood epilepsy (Agarwal, Johnston, & Stafstrom, 2019; Hamdan et al, 2009; Mignot et al, 2016; Parker et al, 2015; Vlaskamp et al, 2019). This debilitating neurodevelopmental disorder is estimated to be responsible for up to 1% of all cases of ID (Berryer et al, 2013).…”

Intellectual disability, the long way from genes to biological mechanisms

“…Moreover, mutations in the cytosolic protein SYNGAP1 (SYNaptic GTPase activating protein) result in a neurodevelopmental disorder termed Mental retardation-type 5 (MRD5, OMIM #612621) with a phenotype consisting of ID, motor impairments, and epilepsy. SYNGAP1 plays critical roles in synaptic development, structure, function, and plasticity and is one of the targets of phosphorylation by CaMKII [53] . This example serves to illustrate the power of identifying pathways towards understanding ID biology.…”