RESUMEN
PURPOSE: Autism spectrum disorders are associated with defects in social response and communication that often occur in the context of intellectual disability. Rett syndrome is one example in which epilepsy, motor impairment, and motor disturbance may co-occur. Mutations in histone demethylases are known to occur in several of these syndromes. Herein, we aimed to identify whether mutations in the candidate histone demethylase JMJD1C (jumonji domain containing 1C) are implicated in these disorders. METHODS: We performed the mutational and functional analysis of JMJD1C in 215 cases of autism spectrum disorders, intellectual disability, and Rett syndrome without a known genetic defect. RESULTS: We found seven JMJD1C variants that were not present in any control sample (~ 6,000) and caused an amino acid change involving a different functional group. From these, two de novo JMJD1C germline mutations were identified in a case of Rett syndrome and in a patient with intellectual disability. The functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. We confirmed that JMJD1C protein is widely expressed in brain regions and that its depletion compromises dendritic activity. CONCLUSIONS: Our findings indicate that mutations in JMJD1C contribute to the development of Rett syndrome and intellectual disability.Genet Med 18 1, 378-385.
Asunto(s)
Discapacidad Intelectual/genética , Histona Demetilasas con Dominio de Jumonji/genética , Mutación , Oxidorreductasas N-Desmetilantes/genética , Síndrome de Rett/genética , Adulto , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Encéfalo/metabolismo , Encéfalo/patología , Secuencia Conservada , Análisis Mutacional de ADN , Femenino , Expresión Génica , Orden Génico , Estudios de Asociación Genética , Sitios Genéticos , Humanos , Discapacidad Intelectual/diagnóstico , Histona Demetilasas con Dominio de Jumonji/química , Histona Demetilasas con Dominio de Jumonji/metabolismo , Masculino , Persona de Mediana Edad , Modelos Moleculares , Neuronas/metabolismo , Oxidorreductasas N-Desmetilantes/química , Oxidorreductasas N-Desmetilantes/metabolismo , Posición Específica de Matrices de Puntuación , Conformación Proteica , Transporte de Proteínas , Síndrome de Rett/diagnósticoRESUMEN
Rett Syndrome is a neurodevelopmental autism spectrum disorder caused by mutations in the gene coding for methyl CpG-binding protein (MeCP2). The disease is characterized by abnormal motor, respiratory, cognitive impairment, and autistic-like behaviors. No effective treatment of the disorder is available. Mecp2 knockout mice have a range of physiological and neurological abnormalities that resemble the human syndrome and can be used as a model to interrogate new therapies. Herein, we show that the combined administration of Levodopa and a Dopa-decarboxylase inhibitor in RTT mouse models is well tolerated, diminishes RTT-associated symptoms, and increases life span. The amelioration of RTT symptomatology is particularly significant in those features controlled by the dopaminergic pathway in the nigrostratium, such as mobility, tremor, and breathing. Most important, the improvement of the RTT phenotype upon use of the combined treatment is reflected at the cellular level by the development of neuronal dendritic growth. However, much work is required to extend the duration of the benefit of the described preclinical treatment.