USP27X variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms

• Type of Material: Article
• Authors: Intisar Koch, Sanford Research; Maya Slovik, Hebrew University of Jerusalem; Yuling Zhang, Shandong University; Bingyu Liu, Shandong University; Martin Rennie, University of Glasgow; Emily Konz, Sanford Research; Benjamin Cogne, Nantes Université; Muhannad Daana, Clalit Health Care Services; Laura Davids, Children’s Healthcare of Atlanta; Illja J. Diets, Radboud University; Nina B. Gold, Massachusetts General Hospital for Children; Alexander M. Holtz, Harvard Medical School; Bertrand Isidor, Nantes Université; Hagar Mor-Shaked, Hebrew University of Jerusalem; Juanita Neira Fresneda, Emory University; Karen Y. Niederhoffer, University of Alberta; Mathilde Nizon, Nantes Université; Rolph Pfundt, Radboud University; M.E.H. Simon, University Medical Center Utrecht; A.P.A. Stegmann, Maastricht University; Maria J. Guillen Sacoto, GeneDx; Marijke Wevers, Radboud University; Tahsin Stefan Barakat, Erasmus MC University; Shira Yanovsky-Dagan, Hadassah Medical Center; Boyko S. Atanassov, Roswell Park Comprehensive Cancer Center; Rachel Toth, University of Dundee; Chengjiang Gao, Shandong University; Francisco Bustos, Sanford Research; Tamar Harel, Hebrew University of Jerusalem
• Language: English
• Date: 2024-01-05
• Publisher: EMBO Press
• Publication Version: Final Published Version
• Copyright Statement: © 2024 Koch et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.26508/lsa.202302258
• Title of Journal or Parent Work: Life Science Alliance
• Volume: 7
• Issue: 3
• Start Page: e202302258
• Grant/Funding Information: This work was funded by the NIH grants R01CA272771 to BS Atanassov, and P30GM145398 to the Histology and Imaging core at Sanford Research. TS Barakat is supported by a ZonMw Vidi, Grant 09150172110002.
• Keywords: hemizygous variants; cell proliferation; XLID105; USP27X; Neurodevelopmental disorders with intellectual disability (ND/ID); deubiquitylase; neural development
• Research Categories: Biology, Neuroscience; Biology, Genetics

Abstract

Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the USP27X gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data. Furthermore, the mechanisms underlying the disorder are unknown. Here, we report 10 new XLID105 individuals from nine families and determine the impact of gene variants on USP27X protein function. Using a combination of clinical genetics, bioinformatics, biochemical, and cell biology approaches, we determined that XLID105 variants alter USP27X protein biology via distinct mechanisms including changes in developmentally relevant protein–protein interactions and deubiquitylating activity. Our data better define the phenotypic spectrum of XLID105 and suggest that XLID105 is driven by USP27X functional disruption. Understanding the pathogenic mechanisms of XLID105 variants will provide molecular insight into USP27X biology and may create the potential for therapy development.