Biochemical analysis of autism-linked mutations in SYNGAP1

  • Awarded: 2018
  • Award Type: Explorer
  • Award #: 595692

Mutations in SYNGAP1 have been identified in individuals diagnosed with autism spectrum disorder (ASD) or forms of intellectual disability. SYNGAP1 is a brain-specific RAS GAP (GTPase activating protein) that negatively regulates Ras family GTPases. Ras is a molecular switch that activates multiple effector pathways, including the RAF-MEK-ERK kinase cascade that controls cell proliferation and differentiation in dividing cells. In neurons, the RAS pathway is activated in response to synaptic signaling, but the precise mechanisms and targets in neurons are less well understood.

RASopathies are a family of developmental syndromes caused by mutations in components of the RAS-ERK signaling pathway and are often associated with cognitive impairments. Inactivating mutations in the RAS GAP, neurofibromin (NF1), cause the RASopathy neurofibromatosis. As SYNGAP1 is a member of the same RAS GAP family, it’s likely that the mutations in SYNGAP1 identified in individuals with ASD also reflect a loss of SYNGAP1 function. In order to assess the effects of ASD-linked SYNGAP1 mutations, Frank McCormick’s laboratory will establish cell- and tissue-based biochemical techniques and perform proteomic studies. These analyses will enable McCormick’s group to address the molecular mechanism by which SYNGAP1 regulates RAS in neurons and the biochemical mechanisms by which pathologic mutations perturb signaling. The results of this work will also provide insights into possible therapeutic intervention of the RAS pathway that may be beneficial in individuals with SYNGAP1 mutations.

Subscribe to our newsletter and receive SFARI funding announcements and news