RESUMEN
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.
Asunto(s)
Trastorno Autístico/genética , Epilepsia/genética , Haploinsuficiencia , Discapacidad Intelectual/genética , Proteínas Activadoras de ras GTPasa/genética , Adolescente , Secuencia de Aminoácidos , Trastorno Autístico/fisiopatología , Western Blotting , Niño , Preescolar , Clonación Molecular , Epilepsia/fisiopatología , Exoma , Quinasas MAP Reguladas por Señal Extracelular/genética , Femenino , Células HEK293 , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Datos de Secuencia Molecular , Mutación Missense , Fenotipo , Fosforilación , Conformación Proteica , Análisis de Secuencia de ADN , Transfección , Proteínas Activadoras de ras GTPasa/metabolismoRESUMEN
We report a recurrent 680-kb deletion within chromosome 15q13.3 in ten individuals, from four unrelated families, with neurodevelopmental phenotypes including developmental delay, mental retardation and seizures. This deletion likely resulted from nonallelic homologous recombination between low-copy repeats on the normal and inverted region of chromosome 15q13.3. Although this deletion also affects OTUD7A, accumulated data suggest that haploinsufficiency of CHRNA7 is causative for the majority of neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome.