Key roles of C2/GAP domains in SYNGAP1-related pathophysiology

Katsanevaki, Danai; Till, Sally M.; Buller-Peralta, Ingrid; Nawaz, Mohammad Sarfaraz; Louros, Susana R.; Kapgal, Vijayakumar; Tiwari, Shashank; Walsh, Darren; Anstey, Natasha J.; Petrović, Nina G.; Cormack, Alison; Salazar-Sanchez, Vanesa; Harris, Anjanette; Farnworth-Rowson, William; Sutherland, Andrew; Watson, Thomas C.; Dimitrov, Siyan; Jackson, Adam D.; Arkell, Daisy; Biswal, Suryanarayan; Dissanayake, Kosala N.; Mizen, Lindsay A.M.; Perentos, Nikolas; Jones, Matt W.; Cousin, Michael A.; Booker, Sam A.; Osterweil, Emily K.; Chattarji, Sumantra; Wyllie, David J.A.; Gonzalez-Sulser, Alfredo; Hardt, Oliver; Wood, Emma R.; Kind, Peter C.

doi:10.1016/j.celrep.2024.114733

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2024

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Cited by 4 publications

References 84 publications

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Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition

Libé-Philippot,

Iwata,

Recupero

et al. 2024

Neuron

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Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition

Libé-Philippot,

Iwata,

Recupero

et al. 2024

Neuron

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Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorders

Bonnycastle,

Kind,

Cousin

2024

Preprint

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The key pathological mechanisms underlying autism spectrum disorders (ASDs) remain relatively undetermined, potentially due to the heterogenous nature of the condition. Targeted studies of a series of monogenic ASDs have revealed postsynaptic dysfunction as a central conserved mechanism. Presynaptic dysfunction is emerging as an additional disease locus in neurodevelopmental disorders, however it is unclear whether this dysfunction drives ASDs or is an adaptation to the altered brain microenvironment. To determine this, we performed a high content analysis of key stages of the synaptic vesicle lifecycle in a series of preclinical models of monogenic ASDs. These models were specifically selected to have perturbations in a diverse palette of genes that were expressed either at the pre- or post-synapse. However, all models displayed a common trait of hyperexcitability. We determined that SV fusion events and SV cargo trafficking were unaffected in all models investigated. However, a key convergent phenotype was revealed, a depression in activity-dependent bulk endocytosis (ADBE). This suggests that the depression in ADBE is a homeostatic mechanism to correct hyperexcitability in the ASD brain.

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Genotype–Phenotype Correlations in SYNGAP1‐Related Mental Retardation Type 5

Hong,

Yuan

2024

Clinical Genetics

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Variants in the SYNGAP1 gene leading to decreased SynGAP protein expression are critical for the pathogenesis of mental retardation type 5 (MRD5). This study aims to explore the relationship between SYNGAP1 genotype and clinical phenotype through an expanded sample size, thereby enhancing the understanding of the specific mechanisms underlying MRD5. Data from previously published cases of patients with SYNGAP1 mutations were collected, and the relationship between genotype and clinical phenotype was analyzed. A total of 246 MRD5 patients were included in the analysis. Among them, 98.7% (224/227) were diagnosed with intellectual disability (ID), 91.6% (208/227) with epilepsy, and 57.3% (137/239) with autism spectrum disorder (ASD). The clinical phenotypes of MRD5 patients were found to be associated with their genotypes. Variants located in exons 1 to 6 may correlate with milder ID and reduced risk of ASD, yet they are more likely to present as refractory epilepsy.

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Key roles of C2/GAP domains in SYNGAP1-related pathophysiology

Cited by 4 publications

References 84 publications

Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition

Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition

Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorders

Genotype–Phenotype Correlations in SYNGAP1‐Related Mental Retardation Type 5

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