title: Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency.
abstract: De novo mutations in SYNGAP1, which codes for a RAS/RAP GTP-activating protein, cause nonsyndromic intellectual disability (NSID). All disease-causing point mutations identified until now in SYNGAP1 are truncating, raising the possibility of an association between this type of mutations and NSID. Here, we report the identification of the first pathogenic missense mutations (c.1084T>C [p.W362R], c.1685C>T [p.P562L]) and three novel truncating mutations (c.283dupC [p.H95PfsX5], c.2212_2213del [p.S738X], and (c.2184del [p.N729TfsX31]) in SYNGAP1 in patients with NSID. A subset of these patients also showed ataxia, autism, and a specific form of generalized epilepsy that can be refractory to treatment. All of these mutations occurred de novo, except c.283dupC, which was inherited from a father who is a mosaic. Biolistic transfection of wild-type SYNGAP1 in pyramidal cells from cortical organotypic cultures significantly reduced activity-dependent phosphorylated extracellular signal-regulated kinase (pERK) levels. In contrast, constructs expressing p.W362R, p.P562L, or the previously described p.R579X had no significant effect on pERK levels. These experiments suggest that the de novo missense mutations, p.R579X, and possibly all the other truncating mutations in SYNGAP1 result in a loss of its function. Moreover, our study confirms the involvement of SYNGAP1 in autism while providing novel insight into the epileptic manifestations associated with its disruption.
authors.affiliation: Centre of Excellence in Neurosciences of Université de Montréal and Sainte-Justine Hospital Research Center, Montréal, Québec, Canada.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Berryer
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Laura L
authors.initials: LL
authors.lastname: Klitten
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
authors.forename: Lionel
authors.initials: L
authors.lastname: Carmant
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.forename: Lysanne
authors.initials: L
authors.lastname: Patry
authors.forename: Sylvia
authors.initials: S
authors.lastname: Dobrzeniecka
authors.forename: Daniel
authors.initials: D
authors.lastname: Rochefort
authors.forename: Mathilde
authors.initials: M
authors.lastname: Neugnot-Cerioli
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Lacaille
authors.forename: Zhiyv
authors.initials: Z
authors.lastname: Niu
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eng
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.forename: Sylvain
authors.initials: S
authors.lastname: Palardy
authors.forename: Céline
authors.initials: C
authors.lastname: Belhumeur
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.forename: Ladonna
authors.initials: L
authors.lastname: Immken
authors.forename: Miriam H
authors.initials: MH
authors.lastname: Beauchamp
authors.forename: Gayle Simpson
authors.initials: GS
authors.lastname: Patel
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tarnopolsky
authors.forename: Klaus
authors.initials: K
authors.lastname: Scheffzek
authors.forename: Helle
authors.initials: H
authors.lastname: Hjalgrim
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.forename: Graziella
authors.initials: G
authors.lastname: Di Cristo
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001321:Autistic Disorder / Q000235:genetics* / Q000503:physiopathology; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D003001:Cloning, Molecular; D004827:Epilepsy / Q000235:genetics* / Q000503:physiopathology; D059472:Exome; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D057895:Haploinsufficiency; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype; D010766:Phosphorylation; D011487:Protein Conformation; D017422:Sequence Analysis, DNA; D014162:Transfection; D020703:ras GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C484739:SYNGAP1 protein, human; D020703:ras GTPase-Activating Proteins; D048049:Extracellular Signal-Regulated MAP Kinases