DNMT3A haploinsufficiency results in behavioral deficits and global epigenomic dysregulation shared across neurodevelopmental disorders

Abstract

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 neurodevelopmental disease-associated DNMT3A mutations. We show that diverse mutations affect different aspects of protein activity yet 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 effects of DNMT3A haploinsufficiency in the brain and uncover disruption of the non-CG methylation pathway as a convergence point across neurodevelopmental disorders.

Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome

“…While movement, coordination, memory, learning, and anxiety are intertwined, untangling these relationships in future studies will be important for understanding specific contributions of individual mutations to phenotypes in DOS patients. This model shows more locomotive deficits and less autism-like behaviors than noted in haploinsufficient mice 39 , suggesting possible specific genotype: phenotype relationships for different Dnmt3a mutations. Furthermore, movement deficits, which may be a consequence of behaviors, may contribute to the weight phenotype (or vice versa), and therefore, may have important implications for the development of obesity in DOS patients.…”

Analysis of 200,000 Exome-Sequenced UK Biobank Subjects Implicates Genes Involved in Increased and Decreased Risk of Hypertension

“…DN-MT3A is a DNA methyltransferase, and non-synonymous variants in it have been reported as causes of 2 different syndromes, Tatton-Brown-Rahman syndrome with overgrowth and intellectual disability and Heyn-Sproul-Jackson syndrome with microcephalic dwarfism, neither of which has hypertension as part of the phenotype [26,27]. Missense variants in DNMT3A have also been reported in autism spectrum disorder, and mice with Dnmt3a haploinsufficiency produced by heterozygous deletion of exon 19 have increased body weight and some behavioural alterations [28]. In a series of 210 patients with an overgrowth syndrome similar to Sotos syndrome but with no NSD1 mutation, 4 had de novo non-synonymous mutations in DNMT3A and 2 had stop variants [29].…”

Analysis of 200,000 exome-sequenced UK Biobank subjects implicates genes involved in increased and decreased risk of hypertension

“…DNMT3A is a DNA methyltransferase and nonsynonymous variants in it have been reported as causes of two different syndromes, Tatton-Brown-Rahman syndrome with overgrowth and intellectual disability and Heyn-Sproul-Jackson syndrome with microcephalic dwarfism, neither of which has hypertension as part of the phenotype (Heyn et al, 2019; Tatton-Brown et al, 2014). Missense variants in DNMT3A have also been reported in autism spectrum disorder and mice with Dnmt3a haploinsufficiency produced by heterozygous deletion of exon 19 have increased body weight and some behavioural alterations (Christian et al, 2020). In a series of 210 patients with an overgrowth syndrome similar to Sotos syndrome but with no NSD1 mutation, four had de novo nonsynonymous mutations in DNMT3A and two had stop variants (Tlemsani et al, 2016).…”