Nature Communications (Jul 2023)
Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders
- Carolina Gracia-Diaz,
- Yijing Zhou,
- Qian Yang,
- Reza Maroofian,
- Paula Espana-Bonilla,
- Chul-Hwan Lee,
- Shuo Zhang,
- Natàlia Padilla,
- Raquel Fueyo,
- Elisa A. Waxman,
- Sunyimeng Lei,
- Garrett Otrimski,
- Dong Li,
- Sarah E. Sheppard,
- Paul Mark,
- Margaret H. Harr,
- Hakon Hakonarson,
- Lance Rodan,
- Adam Jackson,
- Pradeep Vasudevan,
- Corrina Powel,
- Shehla Mohammed,
- Sateesh Maddirevula,
- Hamad Alzaidan,
- Eissa A. Faqeih,
- Stephanie Efthymiou,
- Valentina Turchetti,
- Fatima Rahman,
- Shazia Maqbool,
- Vincenzo Salpietro,
- Shahnaz H. Ibrahim,
- Gabriella di Rosa,
- Henry Houlden,
- Maha Nasser Alharbi,
- Nouriya Abbas Al-Sannaa,
- Peter Bauer,
- Giovanni Zifarelli,
- Conchi Estaras,
- Anna C. E. Hurst,
- Michelle L. Thompson,
- Anna Chassevent,
- Constance L. Smith-Hicks,
- Xavier de la Cruz,
- Alexander M. Holtz,
- Houda Zghal Elloumi,
- M J Hajianpour,
- Claudine Rieubland,
- Dominique Braun,
- Siddharth Banka,
- Genomic England Research Consortium,
- Deborah L. French,
- Elizabeth A. Heller,
- Murielle Saade,
- Hongjun Song,
- Guo-li Ming,
- Fowzan S. Alkuraya,
- Pankaj B. Agrawal,
- Danny Reinberg,
- Elizabeth J. Bhoj,
- Marian A. Martínez-Balbás,
- Naiara Akizu
Affiliations
- Carolina Gracia-Diaz
- Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia
- Yijing Zhou
- Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia
- Qian Yang
- Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania
- Reza Maroofian
- Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London
- Paula Espana-Bonilla
- Department of Structural and Molecular Biology, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC)
- Chul-Hwan Lee
- Department of Biomedical Sciences and Pharmacology, Seoul National University, College of Medicine
- Shuo Zhang
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania
- Natàlia Padilla
- Research Unit in Clinical and Translational Bioinformatics, Vall d’Hebron Institute of Research (VHIR), Universitat Autonoma de Barcelona
- Raquel Fueyo
- Department of Structural and Molecular Biology, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC)
- Elisa A. Waxman
- Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia
- Sunyimeng Lei
- Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia
- Garrett Otrimski
- Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia
- Dong Li
- Center for Applied Genomics, The Children’s Hospital of Philadelphia
- Sarah E. Sheppard
- Center for Applied Genomics, The Children’s Hospital of Philadelphia
- Paul Mark
- Department of Pediatrics, Division of Medical Genetics, Helen DeVos Children’s Hospital, Corewell Health
- Margaret H. Harr
- Center for Applied Genomics, The Children’s Hospital of Philadelphia
- Hakon Hakonarson
- Center for Applied Genomics, The Children’s Hospital of Philadelphia
- Lance Rodan
- Department of Neurology, Boston Children’s Hospital
- Adam Jackson
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester
- Pradeep Vasudevan
- Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust
- Corrina Powel
- Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust
- Shehla Mohammed
- Guy’s Hospital
- Sateesh Maddirevula
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
- Hamad Alzaidan
- Department of Genetics, King Faisal Specialist Hospital and Research Center
- Eissa A. Faqeih
- Section of Medical Genetics, Children’s Specialist Hospital
- Stephanie Efthymiou
- Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London
- Valentina Turchetti
- Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London
- Fatima Rahman
- Developmental and Behavioral Pediatrics, University of Child Health Sciences & The Children’s Hospital
- Shazia Maqbool
- Developmental and Behavioral Pediatrics, University of Child Health Sciences & The Children’s Hospital
- Vincenzo Salpietro
- Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London
- Shahnaz H. Ibrahim
- Department of Pediatrics and Child Health, Aga Khan University Hospital
- Gabriella di Rosa
- Child Neuropsychiatry Unit, Department of Pediatrics, University of Messina
- Henry Houlden
- Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London
- Maha Nasser Alharbi
- Maternity and Children Hospital Buraidah, Qassim Health Cluster
- Nouriya Abbas Al-Sannaa
- John Hopkins Aramco Health Care, Pediatric Services
- Peter Bauer
- Centogene GmbH
- Giovanni Zifarelli
- Centogene GmbH
- Conchi Estaras
- Center for Translational Medicine, Department of Cardiovascular Sciences, Temple University
- Anna C. E. Hurst
- University of Alabama at Birmingham
- Michelle L. Thompson
- HudsonAlpha Institute for Biotechnology
- Anna Chassevent
- Department of Neurogenetics, Neurology and Developmental Medicine Kennedy Krieger Institute
- Constance L. Smith-Hicks
- Department of Neurogenetics, Neurology and Developmental Medicine Kennedy Krieger Institute
- Xavier de la Cruz
- Research Unit in Clinical and Translational Bioinformatics, Vall d’Hebron Institute of Research (VHIR), Universitat Autonoma de Barcelona
- Alexander M. Holtz
- Division of Genetics & Genomics, Boston Children’s Hospital
- Houda Zghal Elloumi
- GeneDx
- M J Hajianpour
- Division of Medical Genetics and Genomics, Department of Pediatrics, Albany Medical College
- Claudine Rieubland
- Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern
- Dominique Braun
- Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern
- Siddharth Banka
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester
- Genomic England Research Consortium
- Deborah L. French
- Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia
- Elizabeth A. Heller
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania
- Murielle Saade
- Department of Structural and Molecular Biology, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC)
- Hongjun Song
- Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania
- Guo-li Ming
- Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania
- Fowzan S. Alkuraya
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
- Pankaj B. Agrawal
- Division of Genetics & Genomics, Boston Children’s Hospital
- Danny Reinberg
- HHMI/NYU Langone School of Medicine
- Elizabeth J. Bhoj
- Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia
- Marian A. Martínez-Balbás
- Department of Structural and Molecular Biology, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC)
- Naiara Akizu
- Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia
- DOI
- https://doi.org/10.1038/s41467-023-39645-5
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 18
Abstract
Abstract Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of two EZH1 missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate that EZH1 variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders.