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, Jingwei Zhao, Wenqi Wang, Aifu Lin, Qingfeng Yan
Abstract
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.