Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders

Authors

Carolina Gracia-Diaz, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
Yijing Zhou, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
Qian Yang, University of Pennsylvania, Philadelphia, PA, USA
Paula Espana-Bonilla, Instituto de Biología Molecular de Barcelona (IBMB)
Chul-Hwan Lee, Seoul National University, College of Medicine, Seoul, South Korea
Shuo Zhang, University of Pennsylvania, Philadelphia, PA, USA
Natàlia Padilla, Universitat Autonoma de Barcelona, Barcelona, Spain
Raquel Fueyo, Instituto de Biología Molecular de Barcelona (IBMB)
Elisa A. Waxman, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
Shahnaz H. Ibrahim, Aga Khan UniversityFollow

Document Type

Article

Department

Paediatrics and Child Health

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

Comments

Pagination are not provided by the author/publisher

Publication (Name of Journal)

Nature Communications

Recommended Citation

Gracia-Diaz, C., Zhou, Y., Yang, Q., Espana-Bonilla, P., Lee, C., Zhang, S., Padilla, N., Fueyo, R., Waxman, E. A., Ibrahim, S. H. (2023). Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders. Nature Communications, 14(1).
Available at: https://ecommons.aku.edu/pakistan_fhs_mc_women_childhealth_paediatr/1402