Article
作者: Herman, Isabella ; Robin, Nathaniel H ; Prouteau, Clément ; Vitalone, Kara ; Rosenfeld, Jill A ; Nedbalova, Pavla ; Ramanathan, Subhadra ; Bradbrook, Samuel ; Bonneau, Dominique ; Costain, Gregory ; Bruel, Ange-Line ; Bi, Weimin ; van der Zwaag, Bert ; Hérissant, Lucas ; Sierra, Roberta Ann ; Goodloe, Dana ; Hennig, Yvonne D ; Yu, Andrea C ; Hancarova, Miroslava ; van Jaarsveld, Richard H ; Kamermans, Alwin ; Longo, Nicola ; Holla, Øystein L ; Cogné, Benjamin ; Monaghan, Kristin G ; Sedlacek, Zdenek ; Nielsen, Shelly ; Lambert, Laëtitia ; Tveten, Kristian ; Abou Jamra, Rami ; Carere, Deanna Alexis ; Staffenberg, David A ; Te Bogt, Emma A M ; Koop, Klaas ; van Oirsouw, Amber S E ; Jouret, Guillaume ; Olney, Ann Haskins ; Oegema, Renske ; Fisher, Heather ; Joset, Pascal ; Miny, Peter ; Scheuerle, Angela E ; van Eerde, Albertien M ; Bodurtha, Joann N ; Glinton, Kevin E ; Caille-Benigni, Charlotte ; Jortveit, Marianne ; Ziegler, Alban ; Fischer, Jan ; Prchalova, Darina ; Palomares Bralo, María ; Pappas, John ; Alali, Abdulrazak ; Vlckova, Marketa ; Riley, Stephanie ; van Gassen, Koen L I ; Isidor, Bertrand ; Perrier, Renee ; Jain, Mahim ; Bendova, Sarka ; van Binsbergen, Ellen ; Vuocolo, Blake ; Gold, June-Anne ; Spiller, Michael ; Mu, Weiyi ; Dyer, Lisa M ; von der Lippe, Charlotte ; Fenckova, Michaela ; Angle, Brad ; Bontempo, Kelly ; Rabin, Rachel ; Stokman, Marijn F ; Balasubramanian, Meena ; Filges, Isabel ; Chen, Yanmin ; Ángeles Gómez-Cano, María ; Porrmann, Joseph ; Johnson, Ivy R ; Prchal, Jan
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.