SYN2 is an autism predisposing gene: Loss-offunction mutations alter synaptic vesicle cycling and axon outgrowth

An increasing number of genes predisposing to autismspectrumdisorders (ASDs) has been identified,many of which are implicated in synaptic function. This 'synaptic autism pathway' notably includes disruption of SYN1 that is associated with epilepsy, autismand abnormal behavior in both human andmicemodels. Synapsins constitute amultigene familyofneuron-specific phosphoproteins (SYN1-3) present in themajorityof synapseswhere they are implicatedinthe regulation ofneurotransmitter release and synaptogenesis.Synapsins I and II, themajor Synisoformsintheadultbrain,displaypartiallyoverlappingfunctionsanddefectsinbothisoformsareassociated with epilepsy and autistic-like behavior inmice. In this study, we show that nonsense (A94fs199X) andmissense (Y236S and G464R)mutations in SYN2 are associated with ASD in humans. The phenotype is apparent inmales. Female carriers ofSYN2mutations areunaffected,suggestingthatSYN2isanotherexample ofautosomal sex-limitedexpressioninASD. WhenexpressedinSYN2 knockoutneurons,wild-typehumanSynII fullyrescuestheSYN2 knockout phenotype, whereas the nonsense mutant is not expressed and the missense mutants are virtually unable tomodify the SYN2 knockout phenotype. These results identify for the first time SYN2 as a novel predisposing gene for ASD and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies ASD.