title: SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function.
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.
authors: Department of Experimental Medicine, National Institute of Neuroscience, University of Genova, Viale Benedetto XV 3, 16132 Genova, Italy.
authors: Anna
authors: A
authors: Fassio
authors: Lysanne
authors: L
authors: Patry
authors: Sonia
authors: S
authors: Congia
authors: Franco
authors: F
authors: Onofri
authors: Amelie
authors: A
authors: Piton
authors: Julie
authors: J
authors: Gauthier
authors: Davide
authors: D
authors: Pozzi
authors: Mirko
authors: M
authors: Messa
authors: Enrico
authors: E
authors: Defranchi
authors: Manuela
authors: M
authors: Fadda
authors: Anna
authors: A
authors: Corradi
authors: Pietro
authors: P
authors: Baldelli
authors: Line
authors: L
authors: Lapointe
authors: Judith
authors: J
authors: St-Onge
authors: Caroline
authors: C
authors: Meloche
authors: Laurent
authors: L
authors: Mottron
authors: Flavia
authors: F
authors: Valtorta
authors: Dang
authors: D
authors: Khoa Nguyen
authors: Guy A
authors: GA
authors: Rouleau
authors: Fabio
authors: F
authors: Benfenati
authors: Patrick
authors: P
authors: Cossette
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D018389:Codon, Nonsense / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D004828:Epilepsies, Partial / Q000235:genetics*; D055786:Gene Knockout Techniques; D006801:Humans; D015151:Immunoblotting; D008126:Lod Score; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D010375:Pedigree; D010766:Phosphorylation; D011792:Quebec; D017422:Sequence Analysis, DNA; D013569:Synapses / Q000235:genetics / Q000473:pathology*; D016704:Synapsins / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D016704:Synapsins; D020928:Mitogen-Activated Protein Kinases