Novel de novo SHANK3 mutation in autistic patients.
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.
Gauthier
Julie
J
Centre of Excellence in Neuromics of Université de Montréal, CHUM Research Centre, Notre-Dame Hospital, Université de Montréal, Montreal, QC, Canada.
Spiegelman
Dan
D
Piton
Amélie
A
Lafrenière
Ronald G
RG
Laurent
Sandra
S
St-Onge
Judith
J
Lapointe
Line
L
Hamdan
Fadi F
FF
Cossette
Patrick
P
Mottron
Laurent
L
Fombonne
Eric
E
Joober
Ridha
R
Marineau
Claude
C
Drapeau
Pierre
P
Rouleau
Guy A
GA
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
D002352:Carrier Proteins; D005819:Genetic Markers; D009419:Nerve Tissue Proteins; D022821:RNA Splice Sites; C492357:SHANK3 protein, human; D011392:Proline