title: Novel de novo SHANK3 mutation in autistic patients.
abstract: A number of studies have confirmed that genetic factors play an important role in autism spectrum disorder (ASD). More recently de novo mutations in the SHANK3 gene, a synaptic scaffolding protein, have been associated with the ASD phenotype. As part of our gene discovery strategy, we sequenced the SHANK3 gene in a cohort of 427 ASD subjects and 190 controls. Here, we report the identification of two putative causative mutations: one being a de novo deletion at an intronic donor splice site and one missense transmitted from an epileptic father. We were able to confirm the deleterious effect of the splice site deletion by RT-PCR using mRNA extracted from cultured lymphoblastoid cells. The missense mutation, a leucine to proline at amino acid position 68, is perfectly conserved across all species examined, and would be predicted to disrupt an alpha-helical domain. These results further support the role of SHANK3 gene disruption in the etiology of ASD.
authors.affiliation: Centre of Excellence in Neuromics of Université de Montréal, CHUM Research Centre, Notre-Dame Hospital, Université de Montréal, Montreal, QC, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Gauthier
authors.forename: Dan
authors.initials: D
authors.lastname: Spiegelman
authors.forename: Amélie
authors.initials: A
authors.lastname: Piton
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Lafrenière
authors.forename: Sandra
authors.initials: S
authors.lastname: Laurent
authors.forename: Judith
authors.initials: J
authors.lastname: St-Onge
authors.forename: Line
authors.initials: L
authors.lastname: Lapointe
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Patrick
authors.initials: P
authors.lastname: Cossette
authors.forename: Laurent
authors.initials: L
authors.lastname: Mottron
authors.forename: Eric
authors.initials: E
authors.lastname: Fombonne
authors.forename: Ridha
authors.initials: R
authors.lastname: Joober
authors.forename: Claude
authors.initials: C
authors.lastname: Marineau
authors.forename: Pierre
authors.initials: P
authors.lastname: Drapeau
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001321:Autistic Disorder / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005819:Genetic Markers; D006801:Humans; D007438:Introns; D008297:Male; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins; D010641:Phenotype; D011392:Proline / Q000378:metabolism; D022821:RNA Splice Sites; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid
chemical_list: D002352:Carrier Proteins; D005819:Genetic Markers; D009419:Nerve Tissue Proteins; D022821:RNA Splice Sites; C492357:SHANK3 protein, human; D011392:Proline