Communicated by Mark H. Paalman
Mutations in SYNGAP1 Cause Intellectual Disability, Autism, and a Specific Form of Epilepsy by Inducing Haploinsufficiency
Article first published online: 12 DEC 2012
© 2012 WILEY PERIODICALS, INC.
Volume 34, Issue 2, pages 385–394, February 2013
How to Cite
Berryer, M. H., Hamdan, F. F., Klitten, L. L., Møller, R. S., Carmant, L., Schwartzentruber, J., Patry, L., Dobrzeniecka, S., Rochefort, D., Neugnot-Cerioli, M., Lacaille, J.-C., Niu, Z., Eng, C. M., Yang, Y., Palardy, S., Belhumeur, C., Rouleau, G. A., Tommerup, N., Immken, L., Beauchamp, M. H., Patel, G. S., Majewski, J., Tarnopolsky, M. A., Scheffzek, K., Hjalgrim, H., Michaud, J. L. and Di Cristo, G. (2013), Mutations in SYNGAP1 Cause Intellectual Disability, Autism, and a Specific Form of Epilepsy by Inducing Haploinsufficiency. Hum. Mutat., 34: 385–394. doi: 10.1002/humu.22248
Contract grant sponsors: Canadian Institute of Health Research; Réseau de Médecine Génétique Appliquée; Scottish Rite Charitable Foundation; FORGE Canada.
- Issue published online: 29 JAN 2013
- Article first published online: 12 DEC 2012
- Accepted manuscript online: 15 NOV 2012 12:29PM EST
- Manuscript Accepted: 31 OCT 2012
- Manuscript Received: 15 JUN 2012
- Canadian Institute of Health Research
- Réseau de Médecine Génétique Appliquée
- Scottish Rite Charitable Foundation; FORGE Canada
- Danish National Research Foundation
- Lundbeck Foundation
- intellectual disability;
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.