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

Intisar Koch, Maya Slovik, Yuling Zhang, Bingyu Liu, Martin Rennie, Emily Konz, Benjamin Cogne, Muhannad Daana, Laura Davids, Illja J. Diets, Nina B. Gold, Alexander M. Holtz, Bertrand Isidor, Hagar Mor-Shaked, Juanita Neira Fresneda, Karen Y. Niederhoffer, Mathilde Nizon, Rolph Pfundt, Meh Simon, Apa StegmannMaria J Guillen Sacoto, Marijke Wevers, Tahsin Stefan Barakat, Shira Yanovsky-Dagan, Boyko S. Atanassov, Rachel Toth, Chengjiang Gao, Francisco Bustos (Lead / Corresponding author), Tamar Harel (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
51 Downloads (Pure)

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.

Original languageEnglish
Article numbere202302258
JournalLife Science Alliance
Volume7
Issue number3
Early online date5 Jan 2024
DOIs
Publication statusPublished - Mar 2024

Keywords

  • Humans
  • Intellectual Disability/genetics
  • Cell Proliferation
  • Computational Biology
  • Neurogenesis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Health, Toxicology and Mutagenesis
  • Plant Science
  • Ecology

Fingerprint

Dive into the research topics of 'USP27X variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms'. Together they form a unique fingerprint.

Cite this