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Mutations in SYNGAP1 Cause Intellectual Disability, Autism, and a Specific Form of Epilepsy by Inducing Haploinsufficiency
Author(s) -
Berryer Martin H.,
Hamdan Fadi F.,
Klitten Laura L.,
Møller Rikke S.,
Carmant Lionel,
Schwartzentruber Jeremy,
Patry Lysanne,
Dobrzeniecka Sylvia,
Rochefort Daniel,
NeugnotCerioli Mathilde,
Lacaille JeanClaude,
Niu Zhiyv,
Eng Christine M.,
Yang Yaping,
Palardy Sylvain,
Belhumeur Céline,
Rouleau Guy A.,
Tommerup Niels,
Immken LaDonna,
Beauchamp Miriam H.,
Patel Gayle Simpson,
Majewski Jacek,
Tarnopolsky Mark A.,
Scheffzek Klaus,
Hjalgrim Helle,
Michaud Jacques L.,
Di Cristo Graziella
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22248
Subject(s) - missense mutation , biology , haploinsufficiency , autism , genetics , epilepsy , mutation , intellectual disability , phenotype , gene , medicine , neuroscience , psychiatry
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 (p ERK ) levels. In contrast, constructs expressing p.W362R, p.P562L, or the previously described p.R579X had no significant effect on p ERK 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.