Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional deficits.

Autor:	Beard DC; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA., Zhang X; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA., Wu DY; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA., Martin JR; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA., Erickson A; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA., Boua JV; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA., Hamagami N; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA., Swift RG; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA., McCullough KB; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA., Ge X; Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA., Bell-Hensley A; Department of Biomedical Engineering, Washington University, St. Louis, MO 63110, USA; Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA., Zheng H; Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA., Palmer CW; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA; Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA., Fuhler NA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA; Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA., Lawrence AB; Department of Pathology and Anatomical Science, University of Missouri School of Medicine, Columbia, MO 65212, USA., Hill CA; Department of Pathology and Anatomical Science, University of Missouri School of Medicine, Columbia, MO 65212, USA., Papouin T; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA., Noguchi KK; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA; Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA., McAlinden A; Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA., Garbow JR; Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA., Dougherty JD; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA., Maloney SE; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA; Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA., Gabel HW; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA; Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: gabelh@wustl.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Nov 28; Vol. 42 (11), pp. 113411. Date of Electronic Publication: 2023 Nov 11.
DOI:	10.1016/j.celrep.2023.113411
Abstrakt:	Phenotypic heterogeneity in monogenic neurodevelopmental disorders can arise from differential severity of variants underlying disease, but how distinct alleles drive variable disease presentation is not well understood. Here, we investigate missense mutations in DNA methyltransferase 3A (DNMT3A), a DNA methyltransferase associated with overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity. We generate a Dnmt3a P900L/+ mouse mimicking a mutation with mild to moderate severity and compare phenotypic and epigenomic effects with a severe R878H mutation. P900L mutants exhibit core growth and behavioral phenotypes shared across models but show subtle epigenomic changes, while R878H mutants display extensive disruptions. We identify mutation-specific dysregulated genes that may contribute to variable disease severity. Shared transcriptomic disruption identified across mutations overlaps dysregulation observed in other developmental disorder models and likely drives common phenotypes. Together, our findings define central drivers of DNMT3A disorders and illustrate how variable epigenomic disruption contributes to phenotypic heterogeneity in neurodevelopmental disease. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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