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

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 neurotransmitterrelease and synaptogenesis. This nonsense mutation was found in all affected individuals froma large French-Canadian family segregating epilepsy and ASDs. Additional mutations in SYN1 (A51G, A550Tand 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 substrateof multiple protein kinases. When expressed in synapsin I (SynI) knockout (KO) neurons, all the D-domainmutants failed in rescuing the impairment in the size and trafficking of synaptic vesicle pools, whereas thewild-type human SynI fully reverted the KO phenotype. Moreover, the nonsense Q555X mutation had a dramaticimpact on phosphorylation by MAPK/Erk and neurite outgrowth, whereas the missense A550T andT567A mutants displayed impaired targeting to nerve terminals. These results demonstrate that SYN1 is anovel predisposing gene to ASDs, in addition to epilepsy, and strengthen the hypothesis that a disturbanceof synaptic homeostasis underlies the pathogenesis of both diseases.