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

Zexiao Jia; Shuxu Yang; Mengyao Li; Zhaoying Lei; Xue Ding; Mingjie Fan; Dixian Wang; Dajiang Xie; Hui Zhou; Yue Qiu; Qianqian Zhuang; Dan Li; Wei Yang; Xuchen Qi; Xiaohui Cang; Jing-Wei Zhao; Wenqi Wang; Aifu Lin; Qingfeng Yan

doi:10.1016/j.isci.2022.105275

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. eCollection 2022 Nov 18.

Authors

Zexiao Jia¹, Shuxu Yang², Mengyao Li¹, Zhaoying Lei¹, Xue Ding¹, Mingjie Fan¹, Dixian Wang³, Dajiang Xie², Hui Zhou¹, Yue Qiu¹, Qianqian Zhuang¹, Dan Li¹, Wei Yang¹, Xuchen Qi², Xiaohui Cang³, Jing-Wei Zhao³, Wenqi Wang⁴, Aifu Lin¹, Qingfeng Yan^{1

5

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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.

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.