RBMX functional retrocopy safeguards brain development in a species-dependent context

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ID: 318941
2026
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Abstract
Abstract Retrotransposition has generated thousands of intronless gene copies in mammalian genomes, yet their contribution to brain development and evolution remains largely unexplored. RBMX encodes an X-linked RNA-binding protein involved in pre-mRNA splicing. RBMX has highly similar retrocopies, RBMXL1, which arose independently in primates and rodents, suggesting convergent evolutionary pressure and potential functional compensation. We identified individuals with RBMX variants through exome sequencing and GeneMatcher. We combined transcriptomic profiling, protein-protein and protein–RNA interaction studies both in human cellular models and mouse embryonic cortices to assess the functional redundancy between RBMX and its retrocopy RBMXL1. Finally, we use mouse genetics to dissect RBMX function and its compensation by RBMXL1 in corticogenesis. Hemizygous RBMX variants lead to neurodevelopmental disorders characterized by intellectual disability and variable brain, ocular, and genital malformations. N-terminal variants include missense changes and in-frame deletions, whereas truncating variants clustered in the final exon. RBMX pathogenic variants disrupt cortical development through both partial loss-of function (C-terminal variants) and gain-of-function (N-terminal variants) mechanisms. Despite severe phenotypes in humans, Rbmx-deficient mice display only mild cortical abnormalities. We demonstrate that RBMX and RBMXL1 share protein and RNA partners and act redundantly in brain development, with RBMXL1 buffering the impact of RBMX deficiency. Together, these findings establish RBMXL1 as a functional paralog of RBMX that is likely buffering deleterious variation in a context- and dosage-dependent manner. More broadly, these results identify retrocopies as active contributors to neurodevelopmental robustness and suggest that functional retrocopies may have facilitated the evolutionary diversification of the mammalian brain.
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Authors Pierre Tilliole, Carolin Mattausch, Peggy Tilly, Elsa Leitão, Lucile Boutaud, Daphné Lehalle, Isabelle An, Emanuela Argilli, Sharon Aufox, Bert Callewaert, P Peterson Charles, Jessica Cinkornpumin, Thomas Courtin, Marco Dalla Vecchia, Erica E. Davis, Boyan Dimitrov, William B. Dobyns, Ekaterina Epifanova, Erwan Grandgirard, Matthieu Jung, Sarah Jurgensmeyer Langas, Sabine Kaya, Boris Keren, Tahir Naeem Khan, Elodie Lejeune, M Li, Yannick Marie, Bastien Morlet, Caroline Nava, William A. Pastor, Damien Plassard, Carlos E Prada, Agnès Rastetter, Noémie Schwaller, Nenad Šestan, Elliott Sherr, Suzanna L. Temple, Jude-Felix Tenywa, Sylvia Tielens, Arie van Haeringen, Helen Whitley, Laurent Nguyen, Laura Steenpaß, Muriel Rhinn, Stephan C. Collins, Delphine Héron, Walid Haouari, Tania Attié‐Bitach, Binnaz Yalcin, Christel Depienne, Juliette D. Godin
Journal Brain research
Year 2026
DOI
10.1093/brain/awag218
URL
https://doi.org/10.1093/brain/awag218
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