USP27X variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms- Tamar Harel
https://pubmed.ncbi.nlm.nih.gov/38182161/
Intisar Koch 1, Maya Slovik 2 3, Yuling Zhang 4, Bingyu Liu 4, Martin Rennie 5, Emily Konz 1, Benjamin Cogne 6 7, Muhannad Daana 8, Laura Davids 9, Illja J Diets 10, Nina B Gold 11 12, Alexander M Holtz 13, Bertrand Isidor 6 7, Hagar Mor-Shaked 2 3, Juanita Neira Fresneda 14, Karen Y Niederhoffer 15, Mathilde Nizon 6 7, Rolph Pfundt 10, Meh Simon 16, Apa Stegmann 17, Maria J Guillen Sacoto 18, Marijke Wevers 10, Tahsin Stefan Barakat 19 20, Shira Yanovsky-Dagan 3, Boyko S Atanassov 21, Rachel Toth 22, Chengjiang Gao 4, Francisco Bustos 23 24, Tamar Harel 25 3
Affiliations Expand
- PMID: 38182161
- PMCID: PMC10770416
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.