RBMX functional retrocopy safeguards brain development

ABSTRACT

Retrotransposition has generated thousands of intronless gene copies in mammalian genomes, yet their contribution to brain development and evolution remains largely unexplored. Here we uncover a critical role for RBMX retrocopy in shaping neurodevelopment and modulating disease. Pathogenic variants in
RBMX
, an X-linked splicing regulator, cause intellectual disability, microcephaly, and cortical malformations. Through integrated human genetic, cellular, and mouse model studies, we show that
RBMX
pathogenic variants disrupt cortical development through both loss- and gain-of-function mechanisms. Surprisingly, despite severe phenotypes in humans,
Rbmx
-deficient mice display only mild cortical abnormalities, a discrepancy likely due to 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 in brain development, with RBMXL1 buffering the impact of
RBMX
deficiency. These findings establish retrocopies as functional paralogs safeguarding neurodevelopment, and suggest that functional RBMX retrocopy could contribute to the robustness and evolutionary diversification of mammalian brain.