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
To further investigate the long-term impact of pre-adoption adversity on international adoptees, externalizing and internalizing symptoms were assessed using a self-report measure at school-age in addition to mothers' reports. The sample consisted of 95 adopted children and their mothers. Children's health and developmental status were assessed soon after arrival in their adoptive family. At age 7, the Dominic Interactive, a self-report measure, was used to evaluate externalizing and internalizing symptoms while mothers completed the CBCL. Children's self-reports were compared to their non-adopted peers'. Adopted children reported more symptoms of specific phobia than their peers. A significant correlation was found between mothers' and children's reports but only for externalizing symptoms. Self-reported symptoms were related to indices of nutritional and psychosocial deprivation at arrival, such as low height/age and weight/height ratios. Our results emphasize the importance of considering international adoptees' perception of their psychological adjustment and the long-term impact of early risk factors.