文章基本信息

标题：A novel NF2 splicing mutant causes neurofibromatosis type 2 via liquid-liquid phase separation with large tumor suppressor and Hippo pathway
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作者：Zexiao Jia ; Shuxu Yang ; Mengyao Li 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：11
页码：1-25
DOI：10.1016/j.isci.2022.105275
语种：English
出版社：Elsevier
摘要：SummaryNeurofibromatosis 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 aNF2c.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.Graphical abstractDisplay OmittedHighlights•NF2c.770-784 deletion is a novel mutation related to Neurofibromatosis type 2•NF2variant forms LLPS in the cytoplasm with LATS and inhibits the Hippo pathway•NF2variant causes an aberrant skipping of exon 8 and reduces NF2 protein level•NF2variant promotes proliferation and tumorigenesis of meningeal cellsClinical genetics; Pathophysiology; Functional aspects of cell biology