A novel NF2 splicing mutant causes neurofibromatosis type 2 via liquid-liquid phase separation with large tumor suppressor and Hippo pathway

  • iScience. 2022 Oct 4;25(11):105275. doi: 10.1016/j.isci.2022.105275.
Zexiao Jia  1 ,  Shuxu Yang  2 ,  Mengyao Li  1 ,  Zhaoying Lei  1 ,  Xue Ding  1 ,  Mingjie Fan  1 ,  Dixian Wang  3 ,  Dajiang Xie  2 ,  Hui Zhou  1 ,  Yue Qiu  1 ,  Qianqian Zhuang  1 ,  Dan Li  1 ,  Wei Yang  1 ,  Xuchen Qi  2 ,  Xiaohui Cang  3 ,  Jing-Wei Zhao  3 ,  Wenqi Wang  4 ,  Aifu Lin  1 ,  Qingfeng Yan  1  5  6
Affiliations
  • 1. College of Life Sciences Zhejiang University, Zhejiang 310058, China.
  • 2. Department of Neurosurgery Sir Run Run Shaw Hospital, School of Medicine Zhejiang University, Zhejiang 310016, China.
  • 3. School of Medicine Zhejiang University, Zhejiang 310058, China.
  • 4. Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
  • 5. Department of Pediatrics, The First Affiliated Hospital, School of Medicine Zhejiang University, Zhejiang 310003, China.
  • 6. Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Zhejiang 310058, China.
PMID: 36300003 DOI: 10.1016/j.isci.2022.105275
Abstract

Neurofibromatosis type 2 is an autosomal dominant multiple neoplasia syndrome and is usually caused by mutations in the neurofibromin 2 (NF2) gene, which encodes a tumor suppressor and initiates the Hippo pathway. However, the mechanism by which NF2 functions in the Hippo pathway isn't fully understood. Here we identified a NF2 c.770-784del mutation from a neurofibromatosis type 2 family. MD simulations showed that this mutation significantly changed the structure of the F3 module of the NF2-FERM domain. Functional assays indicated that the NF2 c.770-784del variant formed LLPS in the cytoplasm with LATS to restrain LATS plasma membrane localization and inactivated the Hippo pathway. Besides, this deletion partly caused a skipping of exon 8 and reduced the protein level of NF2, collectively promoting proliferation and tumorigenesis of meningeal cells. We identified an unrecognized mechanism of LLPS and splicing skipping for the NF2-induced Hippo pathway, which provided new insight into the pathogenesis of neurofibromatosis type 2.

Keywords
Clinical genetics; Functional aspects of cell biology; Pathophysiology.
Products