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- Title
SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function.
- Authors
Fassio, Anna; Patry, Lysanne; Congia, Sonia; Onofri, Franco; Piton, Amelie; Gauthier, Julie; Pozzi, Davide; Messa, Mirko; Defranchi, Enrico; Fadda, Manuela; Corradi, Anna; Baldelli, Pietro; Lapointe, Line; St-Onge, Judith; Meloche, Caroline; Mottron, Laurent; Valtorta, Flavia; Khoa Nguyen, Dang; Rouleau, Guy A; Benfenati, Fabio; Cossette, Patrick
- Abstract
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
Human molecular genetics, 2011, Vol 20, Issue 12, p2297
- ISSN
1460-2083
- Publication type
Journal Article
- DOI
10.1093/hmg/ddr122