This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant. Additional de novo protein-truncating variants and missense variants in the DNMT3A gene were identified in ASD probands from the SPARK cohort (Feliciano et al., 2019) and the Autism Sequencing Consortium (Satterstrom et al., 2020); TADA analysis in both studies identified DNMT3A as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified DNMT3A as a gene reaching exome-wide significance (P < 2.5E-06). Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals. De novo gain-of-function missense variants in the DNMT3A gene were observed in three patients presenting with microcephalic dwarfism and developmental delay (Heyn et al., 2018).
Molecular Function
The protein encoded by this gene is required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. It plays a role in paternal and maternal imprinting.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.
Model Type:
Genetic LOF
Model Genotype:
Homozygous
Mutation:
A 0.3kb region encoding the pc and env motifs of dnmt3a was replaced with a cassette containing an ires-lacz gene and a neo gene. northern blot analysis of total rna showed an absence of transcript in homozygous mutant mice.
Allele Type: Knockout
Strain of Origin: 129S4/SvJae
Genetic Background: 129S4/SvJae
ES Cell Line: NA
Mutant ES Cell Line: J1
Model Source: 33238114
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Mice carrying a constitutive heterozygous deletion of exon 19 of dnmt3a were generated by crossing mice derived from dnmt3a fl/fl strain and cmv-cre (imsr cat# jax:006054, rrid:imsr_jax:006054; balb/cj) mice obtained from the jackson laboratory.
Allele Type: Knockout
Strain of Origin: 129S4/SvJae
Genetic Background: 129S4/SvJae*BALB/cJ
ES Cell Line: NA
Mutant ES Cell Line: J1
Model Source: Kaneda et al., 2004 (Provided by M. Goodell)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The DNMT3A P900L mouse model was generated using single guide RNAs (sgRNAs) to create a cytosine to thymine substitution at chr12:3,907,719. This mutation changed the proline CCG codon into a leucine CTG codon, corresponding to the P904L human mutation. Founders were crossed to C57BL6/J females for 5-10 generations before experimental analysis.
Allele Type: ASD mutation
Strain of Origin: C57BL/6J x CBA
Genetic Background: C57BL6/J
ES Cell Line: N2A
Mutant ES Cell Line: Model Source: Harrison W. Gabel
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Heterozygous mice carry one allele with a guanine to adenine substitution which results in a arginine to histidine mutation in amino acid 878, which corresponds to the R882H human mutation found in patients with acute myeloid leukemia. Mutant male mice were crossed with C57BL6/J female mice.
Allele Type: Humanized mutation
Strain of Origin: C57BL/6NTac
Genetic Background: C57BL6/J
ES Cell Line: iTL IC1
Mutant ES Cell Line: Model Source: Timothy J. Ley
Description: Genes associated with axon guidance and recognition are differentially expressed; reduced expression of asd genes shank2 and shank3, upregulation of shroom3, latrophilin-2; geo: gse147899
Description: Significant acetylation changes at mecp2-repressed enhancers; enhancers within high mca tads show significantly higher increases in acetylation compared with enhancers in other tads; geo: gse147899
Description: Differentially methylated cg and ca regions in regulatory elements in the brain; enhancer dysregulation; mecp2-repressed enhancers are particularly susceptible to mca binding site loss; broad mca-associated derepression of enhancers in cx; geo: gse147899
Description: Tactile discrimination was measured using a textured novel object recognition task. While wildtype mice display preference for novel tactile objects, P900L mutants show no preference.
Description: Heterozygous P900L mice show significantly increased fat mass with no change in lean mass, indicating an obesity phenotype.
Exp Paradigm: EchoMRI
Description: P900L mutant pups make significantly fewer calls when removed from the nest, indicating deficits in early communication behaviors. Mutant pups show decreased volume, and no change in frequency or duration compared to wildtype pups.
Description: Measurement of femur length using X-ray imaging revealed that heterozygote P900L femurs are significantly longer than those of wildtype littermates.
Description: P900L mutant mice show a slight increase in path length upon initial task exposure (first cued trial with visible platform) of the Morris water maze, but they show no difference in cued trials 2-4.
Exp Paradigm: visible platform
Description: RNA sequencing analysis of cerebral cortex from 8-week-old animals was used to define transcriptional alterations in Dnmt3a mutants. P900L mutants displayed significant gene expression changes: 444 upregulated, 182 downregulated.
Description: Enhancer activity was examined using chromatin immunoprecipitation sequencing (ChIP-seq) analysis of histone H3 lysine 27 acetylation (H3K27ac; a histone modification correlated with active enhancers) in the cortex of 8-week-old P900L mutants Quantification of differential acetylation did not detect significantly altered enhancers in the P900L mutant. Enhancers containing hypo-CG differentially methylated regions showed a trend toward upregulation in the P900L mutant.
Description: ChIP-seq measured changes in MeCP2 binding at enhancers genome-wide. Enhancers with a high density of wildtype methyl-CA sites (mCA/kb) exhibited the largest loss of methyl-CA and MeCP2 binding in P900L mutants.
Description: Tactile discrimination was measured using a textured novel object recognition task. While wildtype mice display preference for novel tactile objects, R787H mutants show no preference.
Description: Isolation-induced ultrasonic vocalizations are reduced in R878H mutants compared to WT littermates. Mutants show decreased frequency, but no change in volume or duration, compared to wildtype.
Description: RNA sequencing analysis of cerebral cortex from 8-week-old animals was used to define transcriptional alterations in Dnmt3a mutants. R787H mutants displayed significant gene expression changes: 797 upregulated, 960 downregulated.
Description: Enhancer activity was examined using chromatin immunoprecipitation sequencing (ChIP-seq) analysis of histone H3 lysine 27 acetylation (H3K27ac; a histone modification correlated with active enhancers40) in the cortex of 8-week-old R878H mutants. Quantification of differential acetylation shows 29 upregulated and 29 downregulated enhancers in the R878H mutant. Enhancers containing hypo-CG differentially methylated regions showed significant increases in H3K27ac in the R878H mutant.
Description: ChIP-seq measured changes in MeCP2 binding at enhancers genome-wide. Enhancers with a high density of wildtype methyl-CA sites (mCA/kb) exhibited the largest loss of methyl-CA and MeCP2 binding in R787H mutants.
