PubMed · 40819229
Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder.
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.
Explore related subjects
Keep this discovery
Explore connections, maps & timelines
Amber S E van Oirsouw, Pavla Nedbalova, Miroslava Hancarova, Jan Prchal, Darina Prchalova, Marketa Vlckova, Sarka Bendova, Kristin G Monaghan, Lisa M Dyer, Yanmin Chen, Deanna Alexis Carere, Emma A M Te Bogt, Heather Fisher, Angela E Scheuerle, Stephanie Riley, Mahim Jain, Weiyi Mu, Joann N Bodurtha, Albertien M van Eerde, Marijn F Stokman, Nicola Longo, Meena Balasubramanian, Michael Spiller, Gregory Costain, Charlotte von der Lippe, Kristian Tveten, Marianne Jortveit, Øystein L Holla, Bertrand Isidor, Benjamin Cogné, Kevin E Glinton, Blake Vuocolo, Roberta Ann Sierra, Brad Angle, Kelly Bontempo, Klaas Koop, Rachel Rabin, John Pappas, David A Staffenberg, Pascal Joset, Peter Miny, Isabel Filges, Abdulrazak Alali, Kara Vitalone, Jill A Rosenfeld, Weimin Bi, Samuel Bradbrook, Renee Perrier, Subhadra Ramanathan, June-Anne Gold, María Palomares Bralo, María Ángeles Gómez-Cano, Ann Haskins Olney, Shelly Nielsen, Alban Ziegler, Dominique Bonneau, Clément Prouteau, Ange-Line Bruel, Charlotte Caille-Benigni, Laëtitia Lambert, Andrea C Yu, Nathaniel H Robin, Dana Goodloe, Jan Fischer, Joseph Porrmann, Yvonne D Hennig, Rami Abou Jamra, Isabella Herman, Ivy R Johnson, Lucas Hérissant, Guillaume Jouret, Koen L I van Gassen, Ellen van Binsbergen, Bert van der Zwaag, Alwin Kamermans, Renske Oegema, Zdenek Sedlacek, Michaela Fenckova, Richard H van Jaarsveld. 2025-08-13. Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder.. https://doi.org/10.1016/j.gim.2025.101555
Cite the original work for its findings. Save a collection to share your selection of sources.