RESUMEN
An increasing number of genetic variants have been implicated in autism spectrum disorders (ASDs), and the functional study of such variants will be critical for the elucidation of autism pathophysiology. Here, we report a de novo balanced translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic individual. Using multiple models, such as dental pulp cells, induced pluripotent stem cell (iPSC)-derived neuronal cells and mouse models, we demonstrate that TRPC6 reduction or haploinsufficiency leads to altered neuronal development, morphology and function. The observed neuronal phenotypes could then be rescued by TRPC6 complementation and by treatment with insulin-like growth factor-1 or hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with alterations in this pathway may benefit from these drugs. We also demonstrate that methyl CpG binding protein-2 (MeCP2) levels affect TRPC6 expression. Mutations in MeCP2 cause Rett syndrome, revealing common pathways among ASDs. Genetic sequencing of TRPC6 in 1041 ASD individuals and 2872 controls revealed significantly more nonsynonymous mutations in the ASD population, and identified loss-of-function mutations with incomplete penetrance in two patients. Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model. This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells.
Asunto(s)
Trastorno Autístico/patología , Neuronas/patología , Canales Catiónicos TRPC/metabolismo , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Trastorno Autístico/genética , Trastorno Autístico/fisiopatología , Carboplatino/metabolismo , Diferenciación Celular/genética , Línea Celular , Proliferación Celular/genética , Células Cultivadas , Niño , Modelos Animales de Enfermedad , Embrión de Mamíferos , Etopósido/metabolismo , Regulación de la Expresión Génica/genética , Humanos , Técnicas In Vitro , Células Madre Pluripotentes Inducidas/fisiología , Potenciales Postsinápticos Inhibidores/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitoxantrona/metabolismo , Mutación/genética , Neuronas/metabolismo , Prednisolona/metabolismo , Transducción de Señal/genética , Canales Catiónicos TRPC/genética , Canal Catiónico TRPC6Asunto(s)
Trastorno del Espectro Autista/patología , Regulación de la Expresión Génica/fisiología , Células Madre Multipotentes/metabolismo , Complejos Multiproteicos/metabolismo , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Androstadienos/farmacología , Estudios de Casos y Controles , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Niño , Medio de Cultivo Libre de Suero/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inmunosupresores/farmacología , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Células Madre Multipotentes/efectos de los fármacos , Fosforilación/efectos de los fármacos , Suero/metabolismo , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Factores de Tiempo , WortmaninaRESUMEN
Autism spectrum disorders (ASD) is a group of behaviorally defined neurodevelopmental disabilities characterized by multiple genetic etiologies and a complex presentation. Several studies suggest the involvement of the serotonin system in the development of ASD, but only few have investigated serotonin receptors. We have performed a case-control and a family-based study with 9 polymorphisms mapped to two serotonin receptor genes (HTR1B and HTR2C) in 252 Brazilian male ASD patients of European ancestry. These analyses showed evidence of undertransmission of the HTR1B haplotypes containing alleles -161G and -261A at HTR1B gene to ASD (P=0.003), but no involvement of HTR2C to the predisposition to this disease. Considering the relatively low level of statistical significance and the power of our sample, further studies are required to confirm the association of these serotonin-related genes and ASD.