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Loss-of-function mutation in PRMT9 causes abnormal synapse development by dysregulation of RNA alternative splicing

Author

Listed:
  • Lei Shen

    (Beckman Research Institute, City of Hope Cancer Center)

  • Xiaokuang Ma

    (University of Arizona College of Medicine-Phoenix)

  • Yuanyuan Wang

    (University of California
    The Children’s Hospital of Philadelphia)

  • Zhihao Wang

    (Beckman Research Institute, City of Hope Cancer Center)

  • Yi Zhang

    (Beckman Research Institute, City of Hope Cancer Center)

  • Hoang Quoc Hai Pham

    (Beckman Research Institute, City of Hope Cancer Center
    Beckman Research Institute of City of Hope)

  • Xiaoqun Tao

    (Beckman Research Institute, City of Hope Cancer Center
    Beckman Research Institute of City of Hope)

  • Yuehua Cui

    (University of Arizona College of Medicine-Phoenix)

  • Jing Wei

    (University of Arizona College of Medicine-Phoenix)

  • Dimitri Lin

    (Beckman Research Institute, City of Hope Cancer Center)

  • Tharindumala Abeywanada

    (Beckman Research Institute, City of Hope Cancer Center)

  • Swanand Hardikar

    (The University of Texas MD Anderson Cancer Center)

  • Levon Halabelian

    (University of Toronto)

  • Noah Smith

    (The Children’s Hospital of Philadelphia)

  • Taiping Chen

    (The University of Texas MD Anderson Cancer Center)

  • Dalia Barsyte-Lovejoy

    (University of Toronto)

  • Shenfeng Qiu

    (University of Arizona College of Medicine-Phoenix)

  • Yi Xing

    (The Children’s Hospital of Philadelphia
    University of Pennsylvania
    The Children’s Hospital of Philadelphia)

  • Yanzhong Yang

    (Beckman Research Institute, City of Hope Cancer Center
    Beckman Research Institute of City of Hope)

Abstract

Protein arginine methyltransferase 9 (PRMT9) is a recently identified member of the PRMT family, yet its biological function remains largely unknown. Here, by characterizing an intellectual disability associated PRMT9 mutation (G189R) and establishing a Prmt9 conditional knockout (cKO) mouse model, we uncover an important function of PRMT9 in neuronal development. The G189R mutation abolishes PRMT9 methyltransferase activity and reduces its protein stability. Knockout of Prmt9 in hippocampal neurons causes alternative splicing of ~1900 genes, which likely accounts for the aberrant synapse development and impaired learning and memory in the Prmt9 cKO mice. Mechanistically, we discover a methylation-sensitive protein–RNA interaction between the arginine 508 (R508) of the splicing factor 3B subunit 2 (SF3B2), the site that is exclusively methylated by PRMT9, and the pre-mRNA anchoring site, a cis-regulatory element that is critical for RNA splicing. Additionally, using human and mouse cell lines, as well as an SF3B2 arginine methylation-deficient mouse model, we provide strong evidence that SF3B2 is the primary methylation substrate of PRMT9, thus highlighting the conserved function of the PRMT9/SF3B2 axis in regulating pre-mRNA splicing.

Suggested Citation

  • Lei Shen & Xiaokuang Ma & Yuanyuan Wang & Zhihao Wang & Yi Zhang & Hoang Quoc Hai Pham & Xiaoqun Tao & Yuehua Cui & Jing Wei & Dimitri Lin & Tharindumala Abeywanada & Swanand Hardikar & Levon Halabeli, 2024. "Loss-of-function mutation in PRMT9 causes abnormal synapse development by dysregulation of RNA alternative splicing," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47107-9
    DOI: 10.1038/s41467-024-47107-9
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