Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions.

Animals Cell Line, Tumor Cells, Cultured DNA (Cytosine-5-)-Methyltransferases / genetics DNA Methylation / genetics DNA Methyltransferase 3A DNA Modification Methylases / genetics Dwarfism / genetics Female Gain of Function Mutation / genetics HeLa Cells Histones / genetics Humans Male Mice Mice, Transgenic / genetics Microcephaly / genetics Polycomb-Group Proteins / genetics Protein Binding / genetics Regulatory Sequences, Nucleic Acid / genetics

Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
01 2019
Historique:
received: 12 03 2018
accepted: 10 10 2018
pubmed: 28 11 2018
medline: 25 4 2019
entrez: 28 11 2018
Statut: ppublish

Résumé

DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, which encodes the DNA methyltransferase DNMT3A. These mutations cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2 and H3K36me3, and alter DNA methylation in patient cells. Polycomb-associated DNA methylation valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3a

Identifiants

DOI: 10.1038/s41588-018-0274-x PMID: 30478443 PMC: PMC6520989
pubmed: 30478443
doi: 10.1038/s41588-018-0274-x
pii: 10.1038/s41588-018-0274-x
pmc: PMC6520989
mid: NIHMS1509438
doi:

Substances chimiques

DNMT3A protein, human 0
Dnmt3a protein, mouse 0
Histones 0
Polycomb-Group Proteins 0
histone H3 trimethyl Lys4 0
DNA Modification Methylases EC 2.1.1.-
DNA (Cytosine-5-)-Methyltransferases EC 2.1.1.37
DNA Methyltransferase 3A EC 2.1.1.37

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

96-105

Subventions

Organisme : Wellcome Trust
ID : 200885/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_U127580972
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 103139/Z/13/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00007/5
Pays : United Kingdom
Organisme : NICHD NIH HHS
ID : R01 HD078592
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom

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Auteurs

Patricia Heyn (P)

MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK.

Clare V Logan (CV)

MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK.

Adeline Fluteau (A)

MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK.

Rachel C Challis (RC)

MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK.
ORCID: 0000-0001-9723-5743

Tatsiana Auchynnikava (T)

Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.

Carol-Anne Martin (CA)

MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK.

Joseph A Marsh (JA)

MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK.
ORCID: 0000-0003-4132-0628

Francesca Taglini (F)

MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK.
Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, UK.

Fiona Kilanowski (F)

MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK.

David A Parry (DA)

MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK.
ORCID: 0000-0003-0376-7736

Valerie Cormier-Daire (V)

Department of Medical Genetics, INSERM UMR 1163, Université Paris-Descartes-Sorbonne Paris Cité, Institut Imagine, AP-HP, Hôpital Necker-Enfants Malades, Paris, France.

Chin-To Fong (CT)

Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.

Kate Gibson (K)

Genetic Health Service New Zealand, Christchurch Hospital, Christchurch, New Zealand.

Vivian Hwa (V)

Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
ORCID: 0000-0003-0517-9049

Lourdes Ibáñez (L)

Department of Endocrinology, Pediatric Research Institute Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain.

Stephen P Robertson (SP)

Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
ORCID: 0000-0002-5181-7809

Giorgia Sebastiani (G)

Neonatology Unit, Hospital Clinic-Maternitat, ICGON, BCNatal, University of Barcelona, Barcelona, Spain.

Juri Rappsilber (J)

Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.
Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany.

Robin C Allshire (RC)

Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.
ORCID: 0000-0002-8005-3625

Martin A M Reijns (MAM)

MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK.
ORCID: 0000-0002-5048-2752

Andrew Dauber (A)

Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Division of Endocrinology, Children's National Medical Center, Washington, DC, USA.
ORCID: 0000-0003-4890-0262

Duncan Sproul (D)

MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK. duncan.sproul@igmm.ed.ac.uk.
Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, UK. duncan.sproul@igmm.ed.ac.uk.
ORCID: 0000-0001-6168-4563

Andrew P Jackson (AP)

MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK. andrew.jackson@igmm.ed.ac.uk.
ORCID: 0000-0002-8739-2646

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Gain-of-function DNMT3A mutations cause...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Gain-of-function DNMT3A mutations cause...
questionsmedicales.fr › Cellules › Cellules cultivées › Gain-of-function DNMT3A mutations cause...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › DNA modification methylases › DNA-Cytosine Methylases › DNA (cytosine-5-)-methyltransferase › Gain-of-function DNMT3A mutations cause...
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › Gain-of-function DNMT3A mutations cause...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › DNA modification methylases › DNA-Cytosine Methylases › DNA (cytosine-5-)-methyltransferase › DNA methyltransferase 3A › Gain-of-function DNMT3A mutations cause...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › DNA modification methylases › Gain-of-function DNMT3A mutations cause...
questionsmedicales.fr › Maladies endocriniennes › Nanisme › Gain-of-function DNMT3A mutations cause...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation gain de fonction › Gain-of-function DNMT3A mutations cause...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HeLa › Gain-of-function DNMT3A mutations cause...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Histone › Gain-of-function DNMT3A mutations cause...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Gain-of-function DNMT3A mutations cause...
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