SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth

Anincreasing number of genes predisposing to autism spectrum disorders (ASDs)has been identified, many ofwhich are implicated in synaptic function. This ‘synaptic autism pathway’ notably includes disruption of SYN1thatisassociatedwithepilepsy,autismandabnormalbehaviorinbothhumanandmicemodels.Synapsinscon-stituteamultigenefamilyofneuron-specificphosphoproteins(SYN1-3)presentinthemajorityofsynapseswheretheyareimplicatedintheregulationofneurotransmitterreleaseandsynaptogenesis.SynapsinsIandII,themajorSynisoformsintheadultbrain,displaypartiallyoverlappingfunctionsanddefectsinbothisoformsareassociatedwithepilepsy and autistic-likebehaviorinmice.Inthisstudy,weshowthatnonsense (A94fs199X) andmissense(Y236Sand G464R) mutations in SYN2 are associated withASD inhumans. The phenotype isapparent inmales.FemalecarriersofSYN2mutationsareunaffected,suggestingthatSYN2isanotherexampleofautosomalsex-lim-itedexpressioninASD.WhenexpressedinSYN2knockoutneurons,wild-typehumanSynIIfullyrescuestheSYN2knockout phenotype, whereas the nonsense mutant is not expressed and the missense mutants are virtuallyunabletomodify the SYN2 knockout phenotype. These resultsidentify for the first time SYN2 as a novel predis-posing gene for ASD and strengthen the hypothesis thata disturbance of synaptic homeostasis underlies ASD.