RESUMEN
Germline pathogenic variants in DNMT3A were recently described in patients with overgrowth, obesity, behavioral, and learning difficulties (DNMT3A Overgrowth Syndrome/DOS). Somatic mutations in the DNMT3A gene are also the most common cause of clonal hematopoiesis, and can initiate acute myeloid leukemia (AML). Using whole genome bisulfite sequencing, we studied DNA methylation in peripheral blood cells of 11 DOS patients and found a focal, canonical hypomethylation phenotype, which is most severe with the dominant negative DNMT3AR882H mutation. A germline mouse model expressing the homologous Dnmt3aR878H mutation phenocopies most aspects of the human DOS syndrome, including the methylation phenotype and an increased incidence of spontaneous hematopoietic malignancies, suggesting that all aspects of this syndrome are caused by this mutation.
Asunto(s)
Anomalías Múltiples/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Epigénesis Genética , Anomalías Múltiples/sangre , Adolescente , Adulto , Animales , Conducta Animal , Peso Corporal/genética , Células de la Médula Ósea/metabolismo , Niño , Preescolar , Islas de CpG/genética , Metilación de ADN/genética , ADN Metiltransferasa 3A , Femenino , Perfilación de la Expresión Génica , Mutación de Línea Germinal/genética , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , Humanos , Lactante , Leucemia/genética , Leucemia/patología , Masculino , Ratones Endogámicos C57BL , Obesidad/genética , Fenotipo , Síndrome , Transcripción GenéticaRESUMEN
Mutations in DNA methyltransferase 3A (DNMT3A) have been detected in autism and related disorders, but how these mutations disrupt nervous system function is unknown. Here, we define the effects of DNMT3A mutations associated with neurodevelopmental disease. We show that diverse mutations affect different aspects of protein activity but lead to shared deficiencies in neuronal DNA methylation. Heterozygous DNMT3A knockout mice mimicking DNMT3A disruption in disease display growth and behavioral alterations consistent with human phenotypes. Strikingly, in these mice, we detect global disruption of neuron-enriched non-CG DNA methylation, a binding site for the Rett syndrome protein MeCP2. Loss of this methylation leads to enhancer and gene dysregulation that overlaps with models of Rett syndrome and autism. These findings define the effects of DNMT3A haploinsufficiency in the brain and uncover disruption of the non-CG methylation pathway as a convergence point across neurodevelopmental disorders.
