Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.

Animals Child Drosophila Drosophila melanogaster Haploinsufficiency / genetics Histone-Lysine N-Methyltransferase / genetics Humans Intellectual Disability / genetics Neurodevelopmental Disorders / genetics

Journal

Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835

Informations de publication

Date de publication:
06 2021
Historique:
received: 03 05 2019
accepted: 01 04 2020
revised: 01 04 2020
pubmed: 30 4 2020
medline: 12 10 2021
entrez: 30 4 2020
Statut: ppublish

Résumé

Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

Identifiants

DOI: 10.1038/s41380-020-0725-5 PMID: 32346159
pubmed: 32346159
doi: 10.1038/s41380-020-0725-5
pii: 10.1038/s41380-020-0725-5
doi:

Substances chimiques

Histone-Lysine N-Methyltransferase EC 2.1.1.43
Setd1A protein, human EC 2.1.1.43

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2013-2024

Subventions

Organisme : Medical Research Council
ID : MR/P009085/1
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG009141
Pays : United States

Informations de copyright

© 2020. The Author(s), under exclusive licence to Springer Nature Limited.

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Auteurs

Joost Kummeling (J)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Diante E Stremmelaar (DE)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Nicholas Raun (N)

Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada.
Department of Physiology and Pharmacology, The University of Western Ontario, London, ON, Canada.

Margot R F Reijnders (MRF)

Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6229 ER, Maastricht, The Netherlands.
ORCID: 0000-0002-6379-7147

Marjolein H Willemsen (MH)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Martina Ruiterkamp-Versteeg (M)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Marga Schepens (M)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Calvin C O Man (CCO)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Christian Gilissen (C)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
ORCID: 0000-0003-1693-9699

Megan T Cho (MT)

GeneDx, Gaithersburg, MD, 20877, USA.

Kirsty McWalter (K)

GeneDx, Gaithersburg, MD, 20877, USA.
ORCID: 0000-0002-1654-9036

Margje Sinnema (M)

Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6229 ER, Maastricht, The Netherlands.

James W Wheless (JW)

Division of Pediatric Neurology, University of Tennessee Health Science Center, Memphis, TN, USA.
Neuroscience Institute & Le Bonheur Comprehensive Epilepsy Program, Le Bonheur Children's Hospital, Memphis, TN, USA.

Marleen E H Simon (MEH)

Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Casie A Genetti (CA)

Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA.
The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.

Alicia M Casey (AM)

Division of Pulmonary and Respiratory Diseases, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.

Paulien A Terhal (PA)

Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Jasper J van der Smagt (JJ)

Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Koen L I van Gassen (KLI)

Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Pascal Joset (P)

Institute of Medical Genetics, University of Zurich, Schlieren, 8952, Zurich, Switzerland.

Angela Bahr (A)

Institute of Medical Genetics, University of Zurich, Schlieren, 8952, Zurich, Switzerland.

Katharina Steindl (K)

Institute of Medical Genetics, University of Zurich, Schlieren, 8952, Zurich, Switzerland.

Anita Rauch (A)

Institute of Medical Genetics, University of Zurich, Schlieren, 8952, Zurich, Switzerland.
ORCID: 0000-0003-2930-3163

Elmar Keller (E)

Division of Neuropediatrics, Cantonal Hospital Graubuenden, Chur, Switzerland.

Annick Raas-Rothschild (A)

Institute of Rare Disease, Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.

David A Koolen (DA)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Pankaj B Agrawal (PB)

Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA.
The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.

Trevor L Hoffman (TL)

Regional Department of Genetics, Southern California Kaiser Permanente Medical Group, 1188N. Euclid Street, Anaheim, CA, 92801, USA.

Nina N Powell-Hamilton (NN)

Division of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, DE, 19803, USA.
Department of Pathology and Laboratory Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.

Isabelle Thiffault (I)

Center for Pediatric Genomic Medicine, Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.
Division of Clinical Genetics, Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.

Kendra Engleman (K)

Department of Pediatrics, Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.

Dihong Zhou (D)

Department of Pediatrics, Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.

Olaf Bodamer (O)

Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA.

Julia Hoefele (J)

Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Korbinian M Riedhammer (KM)

Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
ORCID: 0000-0002-7503-5801

Eva M C Schwaibold (EMC)

Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.

Velibor Tasic (V)

Medical School Skopje, University Children's Hospital, Skopje, North Macedonia.
ORCID: 0000-0002-3377-1245

Dirk Schubert (D)

Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
ORCID: 0000-0002-1202-4363

Deniz Top (D)

Department of Pediatrics, Dalhousie University, Halifax, NS, Canada.

Rolph Pfundt (R)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Martin R Higgs (MR)

Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.

Jamie M Kramer (JM)

Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada.
Department of Physiology and Pharmacology, The University of Western Ontario, London, ON, Canada.

Tjitske Kleefstra (T)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. Tjitske.Kleefstra@radboudumc.nl.

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Classifications MeSH

Recherchemedicale.com › Eucaryotes › Animaux › Characterization of SETD1A haploinsufficiency...
Recherchemedicale.com › Personnes › Tranches d'âge › Enfant › Characterization of SETD1A haploinsufficiency...
Recherchemedicale.com › Eucaryotes › Animaux › Invertébrés › Arthropodes › Insectes › Pterygota › Neoptera › Holometabola › Diptera › Drosophilidae › Drosophila › Characterization of SETD1A haploinsufficiency...
Recherchemedicale.com › Eucaryotes › Animaux › Invertébrés › Arthropodes › Insectes › Pterygota › Neoptera › Holometabola › Diptera › Drosophilidae › Drosophila › Drosophila melanogaster › Characterization of SETD1A haploinsufficiency...
Recherchemedicale.com › Phénomènes génétiques › Génotype › Dosage génique › Haploinsuffisance › Characterization of SETD1A haploinsufficiency...
Recherchemedicale.com › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › Protein Methyltransferases › Histone méthyltransférases › Histone-lysine N-methyltransferase › Characterization of SETD1A haploinsufficiency...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Characterization of SETD1A haploinsufficiency...
Recherchemedicale.com › Troubles mentaux › Troubles du développement neurologique › Déficience intellectuelle › Characterization of SETD1A haploinsufficiency...
Recherchemedicale.com › Troubles mentaux › Troubles du développement neurologique › Characterization of SETD1A haploinsufficiency...