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Mol Cell Neurosci. 2018 Sep;91:140-150. doi: 10.1016/j.mcn.2018.03.008. Epub 2018 Mar 24.

Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders.

Author information

1
Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, United States.
2
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, United States.
3
Mouse Imaging Centre, Hospital for Sick Children, Toronto, ONT, Canada.
4
Mouse Imaging Centre, Hospital for Sick Children, Toronto, ONT, Canada; Medical Biophysics, University of Toronto, Toronto, ONT, Canada.
5
Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, United States; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, United States. Electronic address: grumbaug@scripps.edu.

Abstract

SYNGAP1 loss-of-function variants are causally associated with intellectual disability, severe epilepsy, autism spectrum disorder and schizophrenia. While there are hundreds of genetic risk factors for neurodevelopmental disorders (NDDs), this gene is somewhat unique because of the frequency and penetrance of loss-of-function variants found in patients combined with the range of brain disorders associated with SYNGAP1 pathogenicity. These clinical findings indicate that SYNGAP1 regulates fundamental neurodevelopmental processes that are necessary for brain development. Here, we describe four phenotypic domains that are controlled by Syngap1 expression across vertebrate species. Two domains, the maturation of cognitive functions and maintenance of excitatory-inhibitory balance, are defined exclusively through a review of the current literature. Two additional domains are defined by integrating the current literature with new data indicating that SYNGAP1/Syngap1 regulates innate survival behaviors and brain structure. These four phenotypic domains are commonly disrupted in NDDs, suggesting that a deeper understanding of developmental Syngap1 functions will be generalizable to other NDDs of known or unknown etiology. Therefore, we discuss the known molecular and cellular functions of Syngap1 and consider how these functions may contribute to the emergence of disease-relevant phenotypes. Finally, we identify major unexplored areas of Syngap1 neurobiology and discuss how a deeper understanding of this gene may uncover general principles of NDD pathobiology.

KEYWORDS:

Autism spectrum disorder; Circuits; Cognitive impairment; Epilepsy; Intellectual disability; Microcephaly; Neurodevelopment; SynGAP; Synapse; Syngap1

PMID:
29580901
PMCID:
PMC6128754
DOI:
10.1016/j.mcn.2018.03.008
[Indexed for MEDLINE]
Free PMC Article

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