Dataset Information

Dual molecular mechanisms and functional compensation by RBMXL1 retrocopy underlie RBMX-associated neurodevelopmental syndrome

ABSTRACT: Genetic variants in RBMX may cause X-linked neurodevelopmental syndromes, but their pathogenicity and mechanisms remain unclear. Here, we provide definitive evidence from nine unrelated families that RBMX variants lead to neurodevelopmental disorders characterised by intellectual disability, brain malformations, microcephaly, and microphthalmia. Combining in vitro and in vivo experiments in human and mouse models, we show that RBMX pathogenic variants disrupt cortical development through both loss- and gain-of-function mechanisms. Despite severe phenotypes in humans, Rbmx-deficient mice display only mild cortical abnormalities, which we attribute to partial compensation by Rbmxl1, a retrocopy that arose independently in mice and humans. We demonstrate that RBMX and RBMXL1 share protein and RNA partners and act redundantly during brain development, with RBMXL1 buffering the effect of RBMX loss. Our findings reveal that RBMX-related neurodevelopmental syndromes result from the interplay of opposing molecular mechanisms and retrocopy compensation, highlighting a previously unrecognized role for retrocopies in modulating disease severity.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Cell Culture

SUBMITTER: Bastien Morlet

LAB HEAD: Dr Juliette D. Godin

PROVIDER: PXD066823 | Pride | 2026-07-28

REPOSITORIES: Pride

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Publications

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

Tilliole Pierre P Mattausch Carolin C Tilly Peggy P Leitão Elsa E Boutaud Lucile L Lehalle Daphné D An Isabelle I Argilli Emanuela E Aufox Sharon S Callewaert Bert B Charles Perrine P Cinkornpumin Jessica K JK Courtin Thomas T Vecchia Marco Dalla MD Davis Erica E EE Dimitrov Boyan Ivanov BI Dobyns William W Epifanova Ekaterina E Grandgirard Erwan E Jung Matthieu M Jurgensmeyer Langas Sarah S Kaya Sabine S Keren Boris B Khan Tahir N TN Lejeune Elodie E Li Mingfeng M Marie Yannick Y Morlet Bastien B Nava Caroline C Pastor William A WA Plassard Damien D Prada Carlos E CE Rastetter Agnès A Schwaller Noémie N Sestan Nenad N Sherr Elliott E Temple Suzanna L SL Tenywa Jude-Felix JF Tielens Sylvia S van Haeringen Arie A Whitley Helen H Nguyen Laurent L Steenpaß Laura L Rhinn Muriel M Collins Stephan C SC Héron Delphine D Cormier-Daire Valerie V Attie-Bitach Tania T Yalcin Binnaz B Depienne Christel C Godin Juliette D JD

Brain : a journal of neurology 20260626

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 sequencin ...[more]

PMID: 42360281

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