Amelie Piton

Publications (2)15.44 Total impact

• Article: SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function.

  Anna Fassio, Lysanne Patry, Sonia Congia, Franco Onofri, Amelie Piton, Julie Gauthier, Davide Pozzi, Mirko Messa, Enrico Defranchi, Manuela Fadda, [......], Pietro Baldelli, Line Lapointe, Judith St-Onge, Caroline Meloche, Laurent Mottron, Flavia Valtorta, Dang Khoa Nguyen, Guy A Rouleau, Fabio Benfenati, Patrick Cossette
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  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.
  Human Molecular Genetics 03/2011; 20(12):2297-307. · 7.64 Impact Factor
• Source

  Available from: Anthony P Monaco

  Article: Disruption at the PTCHD1 Locus on Xp22.11 in Autism spectrum disorder and intellectual disability.

  Abdul Noor, Annabel Whibley, Christian R Marshall, Peter J Gianakopoulos, Amelie Piton, Andrew R Carson, Marija Orlic-Milacic, Anath C Lionel, Daisuke Sato, Dalila Pinto, [......], Jozef Gecz, Angela F Brady, Charles E Schwartz, Russell J Schachar, Anthony P Monaco, Guy A Rouleau, Chi-Chung Hui, F Lucy Raymond, Stephen W Scherer, John B Vincent
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  ABSTRACT: Autism is a common neurodevelopmental disorder with a complex mode of inheritance. It is one of the most highly heritable of the complex disorders, although the underlying genetic factors remain largely unknown. Here, we report mutations in the X-chromosome PTCHD1 (patched-related) gene in seven families with autism spectrum disorder (ASD) and in three families with intellectual disability. A 167-kilobase microdeletion spanning exon 1 was found in two brothers, one with ASD and the other with a learning disability and ASD features; a 90-kilobase microdeletion spanning the entire gene was found in three males with intellectual disability in a second family. In 900 probands with ASD and 208 male probands with intellectual disability, we identified seven different missense changes (in eight male probands) that were inherited from unaffected mothers and not found in controls. Two of the ASD individuals with missense changes also carried a de novo deletion at another ASD susceptibility locus (DPYD and DPP6), suggesting complex genetic contributions. In additional males with ASD, we identified deletions in the 5' flanking region of PTCHD1 that disrupted a complex noncoding RNA and potential regulatory elements; equivalent changes were not found in male control individuals. Thus, our systematic screen of PTCHD1 and its 5' flanking regions suggests that this locus is involved in ~1% of individuals with ASD and intellectual disability.
  Science translational medicine 09/2010; 2(49):49ra68. · 7.80 Impact Factor