Mutations in JMJD1C are involved in Rett syndrome and intellectual disability

Mauricio A. Sáez, Juana Fernández-Rodríguez, Catia Moutinho, Jose V. Sanchez-Mut, Antonio Gomez, Enrique Vidal, Paolo Petazzi, Karolina Szczesna, Paula Lopez-Serra, Mario Lucariello, Patricia Lorden, Raul Delgado-Morales, Olga J. De La Caridad, Dori Huertas, Josep L. Gelpí, Modesto Orozco, Adriana López-Doriga, Montserrat Milà, Luís A. Perez-Jurado, Mercedes PinedaJudith Armstrong, Conxi Lázaro, Manel Esteller

Resultado de la investigación: Contribución a una revistaArtículo

18 Citas (Scopus)

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.

Idioma originalInglés
Páginas (desde-hasta)378-385
Número de páginas8
PublicaciónGenetics in Medicine
Volumen18
N.º4
DOI
EstadoPublicada - 1 abr 2016

Áreas temáticas de ASJC Scopus

  • Genética (clínica)

Huella Profundice en los temas de investigación de 'Mutations in JMJD1C are involved in Rett syndrome and intellectual disability'. En conjunto forman una huella única.

  • Citar esto

    Sáez, M. A., Fernández-Rodríguez, J., Moutinho, C., Sanchez-Mut, J. V., Gomez, A., Vidal, E., Petazzi, P., Szczesna, K., Lopez-Serra, P., Lucariello, M., Lorden, P., Delgado-Morales, R., De La Caridad, O. J., Huertas, D., Gelpí, J. L., Orozco, M., López-Doriga, A., Milà, M., Perez-Jurado, L. A., ... Esteller, M. (2016). Mutations in JMJD1C are involved in Rett syndrome and intellectual disability. Genetics in Medicine, 18(4), 378-385. https://doi.org/10.1038/gim.2015.100