Speaker
Description
"SYNGAP1 syndrome is a rare neurodevelopmental disorder caused by heterozygous de novo mutations in the SYNGAP1 gene. Affected individuals present with a complex clinical phenotype, including intellectual disability, developmental epileptic encephalopathy, autism spectrum disorder, and other comorbidities. SYNGAP1 encodes SynGAP, a Ras GTPase-activating protein critical for excitatory synapse formation, maturation, and plasticity. Beyond its well-established synaptic role, emerging evidence suggests a broader function in early brain development. However, the mechanisms linking SYNGAP1 dysfunction to the clinical heterogeneity remain poorly understood.
We hypothesize that SYNGAP1 variants of different nature may underlie the diverse spectrum of neurodevelopmental impairments observed in patients. Investigating patient-specific mutations may provide insights into genotype–phenotype correlations and support the development of personalized therapeutic strategies.
To address this, we reprogrammed fibroblasts from patients carrying two distinct SYNGAP1 mutations into induced pluripotent stem cells. From these lines, we generated both 2D and 3D in vitro models to recapitulate early stages of brain development and study neural circuit formation. Our analyses revealed that the two mutations differentially affect SYNGAP1 mRNA stability. Using early brain organoids, we observed variant-dependent alterations in neural rosette organization and progenitor proliferation. In parallel, we derived 2D cortical neurons and tracked network maturation over time, detecting an accelerated development of neuronal circuits in SYNGAP1-mutant lines. Additionally, we identified changes in mitochondrial morphology and dynamics during early neurodevelopment, suggesting a possible role for SYNGAP1 in regulating mitochondrial function.
Together, our findings point to both synaptic and metabolic contributions to SYNGAP1-related pathophysiology and support the use of patient-specific stem cell models to unravel mutation-specific mechanisms. This approach offers a promising avenue toward the development of targeted, stratified therapeutic strategies."
| Author(s) | Alimandi G1*, Giovenale AMG2, Lorenzini S1, Spalice A3, D’Arrigo S4, Rosati J2, Di Angelantonio S1, Basilico B1 |
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| Affiliation(s) | "1 Dept. Of Physiology and Pharmacology, Sapienza University of Rome, Italy 2 Fondazione IRCCS Casa Sollievo della Sofferenza, Italy 3 Dept. of Mother-Child, Urological Science, Sapienza University of Rome, Italy 4 Dept. of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico ""Carlo Besta"", Italy" |
