TY - JOUR

T1 - Mutations in SYNGAP1 Cause Intellectual Disability, Autism, and a Specific Form of Epilepsy by Inducing Haploinsufficiency

AU - Berryer, Martin H

AU - Hamdan, Fadi F

AU - Klitten, Laura L

AU - Møller, Rikke S

AU - Carmant, Lionel

AU - Schwartzentruber, Jeremy

AU - Patry, Lysanne

AU - Dobrzeniecka, Sylvia

AU - Rochefort, Daniel

AU - Neugnot-Cerioli, Mathilde

AU - Lacaille, Jean-Claude

AU - Niu, Zhiyv

AU - Eng, Christine M

AU - Yang, Yaping

AU - Palardy, Sylvain

AU - Belhumeur, Céline

AU - Rouleau, Guy A

AU - Tommerup, Niels

AU - Immken, Ladonna

AU - Beauchamp, Miriam H

AU - Patel, Gayle Simpson

AU - Majewski, Jacek

AU - Tarnopolsky, Mark A

AU - Scheffzek, Klaus

AU - Hjalgrim, Helle

AU - Michaud, Jacques L

AU - Di Cristo, Graziella

N1 - © 2012 WILEY PERIODICALS, INC.

PY - 2013/2

Y1 - 2013/2

N2 - 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.

AB - 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.

U2 - 10.1002/humu.22248

DO - 10.1002/humu.22248

M3 - Journal article

C2 - 23161826

VL - 34

SP - 385

EP - 394

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 2

ER -