SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function

Hum Mol Genet. 2011 Jun 15;20(12):2297-307. doi: 10.1093/hmg/ddr122. Epub 2011 Mar 25.


Several genes predisposing to autism spectrum disorders (ASDs) with or without epilepsy have been identified, many of which are implicated in synaptic function. Here we report a Q555X mutation in synapsin 1 (SYN1), an X-linked gene encoding for a neuron-specific phosphoprotein implicated in the regulation of neurotransmitter release and synaptogenesis. This nonsense mutation was found in all affected individuals from a large French-Canadian family segregating epilepsy and ASDs. Additional mutations in SYN1 (A51G, A550T and T567A) were found in 1.0 and 3.5% of French-Canadian individuals with autism and epilepsy, respectively. The majority of these SYN1 mutations were clustered in the proline-rich D-domain which is substrate of multiple protein kinases. When expressed in synapsin I (SynI) knockout (KO) neurons, all the D-domain mutants failed in rescuing the impairment in the size and trafficking of synaptic vesicle pools, whereas the wild-type human SynI fully reverted the KO phenotype. Moreover, the nonsense Q555X mutation had a dramatic impact on phosphorylation by MAPK/Erk and neurite outgrowth, whereas the missense A550T and T567A mutants displayed impaired targeting to nerve terminals. These results demonstrate that SYN1 is a novel predisposing gene to ASDs, in addition to epilepsy, and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies the pathogenesis of both diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Autistic Disorder / genetics*
  • Base Sequence
  • COS Cells
  • Chlorocebus aethiops
  • Codon, Nonsense / genetics*
  • Electrophoresis, Polyacrylamide Gel
  • Epilepsies, Partial / genetics*
  • Gene Knockout Techniques
  • Humans
  • Immunoblotting
  • Lod Score
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Sequence Data
  • Neurons / metabolism
  • Pedigree
  • Phosphorylation
  • Quebec
  • Sequence Analysis, DNA
  • Synapses / genetics
  • Synapses / pathology*
  • Synapsins / genetics*


  • Codon, Nonsense
  • Synapsins
  • Mitogen-Activated Protein Kinases