title: SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth.
abstract: An increasing number of genes predisposing to autism spectrum disorders (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, autism and abnormal behavior in both human and mice models. Synapsins constitute a multigene family of neuron-specific phosphoproteins (SYN1-3) present in the majority of synapses where they are implicated in the regulation of neurotransmitter release and synaptogenesis. Synapsins I and II, the major Syn isoforms in the adult brain, display partially overlapping functions and defects in both isoforms are associated with epilepsy and autistic-like behavior in mice. In this study, we show that nonsense (A94fs199X) and missense (Y236S and G464R) mutations in SYN2 are associated with ASD in humans. The phenotype is apparent in males. Female carriers of SYN2 mutations are unaffected, suggesting that SYN2 is another example of autosomal sex-limited expression in ASD. When expressed in SYN2  knockout neurons, wild-type human Syn II fully rescues the SYN2 knockout phenotype, whereas the nonsense mutant is not expressed and the missense mutants are virtually unable to modify 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.
authors: Department of Experimental Medicine, University of Genova, Viale Benedetto XV 3, Genova 16132, Italy.
authors: Anna
authors: A
authors: Corradi
authors: Manuela
authors: M
authors: Fadda
authors: Amélie
authors: A
authors: Piton
authors: Lysanne
authors: L
authors: Patry
authors: Antonella
authors: A
authors: Marte
authors: Pia
authors: P
authors: Rossi
authors: Maxime
authors: M
authors: Cadieux-Dion
authors: Julie
authors: J
authors: Gauthier
authors: Line
authors: L
authors: Lapointe
authors: Laurent
authors: L
authors: Mottron
authors: Flavia
authors: F
authors: Valtorta
authors: Guy A
authors: GA
authors: Rouleau
authors: Anna
authors: A
authors: Fassio
authors: Fabio
authors: F
authors: Benfenati
authors: Patrick
authors: P
authors: Cossette
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology*; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000378:metabolism; D018389:Codon, Nonsense; D005260:Female; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism; D016704:Synapsins / Q000235:genetics*; D013572:Synaptic Vesicles / Q000378:metabolism / Q000473:pathology*
chemical_list: D018389:Codon, Nonsense; D016704:Synapsins
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