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

DOI
https://doi.org/10.1038/s41467-023-39645-5
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 18

Abstract

Read online

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.