Publication Date
11-1-2025
Journal
Genetics in Medicine
DOI
10.1016/j.gim.2025.101555
PMID
40819229
Abstract
Purpose: XPO1 functions in key cellular processes, including nucleo-cytoplasmic export and mitosis. The gene is deleted in a subset of patients with the 2p15p16.1 microdeletion syndrome; however, no monogenic XPO1-related disorder has been described to date.
Methods: We collected clinical data of individuals with de novo XPO1 variants through online matchmaking. We used Drosophila to study XPO1 function in development and habituation learning.
Results: A total of 22 individuals met the criteria to be included in the main study cohort. Of these, half have putative loss-of-function variants, and half have coding variants (10 missense and 1 in-frame deletion variant). We found an overlapping phenotype, consistent with a monogenic neurodevelopmental disorder. We demonstrate XPO1 functions in development by ubiquitous and neuron-specific knockdown in Drosophila. GABAergic neuron specific knockdown flies demonstrated impaired habituation.
Conclusion: Our results establish XPO1 as a novel dominant monogenic neurodevelopmental disorder gene and demonstrate a central role for XPO1 in development.
Keywords
Exportin 1 Protein, Humans, Receptors, Cytoplasmic and Nuclear, Karyopherins, Animals, Neurodevelopmental Disorders, Female, Male, Child, Drosophila, Phenotype, Drosophila melanogaster, Adult, Adolescent, Child, Preschool, Dominant inheritance. Habituation. Mendelian disorders. Monogenic NDD. XPO1
Published Open-Access
yes
Recommended Citation
van Oirsouw, Amber S E; Nedbalova, Pavla; Hancarova, Miroslava; et al., "Pathogenic XPO1 Variants Cause a Dominant Neurodevelopmental Disorder" (2025). Faculty and Staff Publications. 4904.
https://digitalcommons.library.tmc.edu/baylor_docs/4904
Included in
Health Services Research Commons, Medical Cell Biology Commons, Medical Molecular Biology Commons, Medical Specialties Commons, Microbiology Commons