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JMG, JGM, Mice, Animals, Transcriptome, Retina, Central Nervous System, Phenotype, Gait, Unfolded Protein Response, Nuclear Receptor Subfamily 1, Group F, Member 2

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G3 (Bethesda). 2023;13(8):jkad131.







This work was supported by NIGMS T32 GM132006-01 to the University of Maine PIs: L. Liaw and C. Henry (GCM), F32 EY022825 (National Eye Institute to ALDT), NIH OD021325 (Office of the Director to LGR), NIH R37NS054154 (National Institute of Neurological Disorders and Stroke to RWB).


The Retinoid-related orphan receptor beta (RORβ) gene encodes a developmental transcription factor and has 2 predominant isoforms created through alternative first exon usage; one specific to the retina and another present more broadly in the central nervous system, particularly regions involved in sensory processing. RORβ belongs to the nuclear receptor family and plays important roles in cell fate specification in the retina and cortical layer formation. In mice, loss of RORβ causes disorganized retina layers, postnatal degeneration, and production of immature cone photoreceptors. Hyperflexion or "high-stepping" of rear limbs caused by reduced presynaptic inhibition by Rorb-expressing inhibitory interneurons of the spinal cord is evident in RORβ-deficient mice. RORβ variants in patients are associated with susceptibility to various neurodevelopmental conditions, primarily generalized epilepsies, but including intellectual disability, bipolar, and autism spectrum disorders. The mechanisms by which RORβ variants confer susceptibility to these neurodevelopmental disorders are unknown but may involve aberrant neural circuit formation and hyperexcitability during development. Here we report an allelic series in 5 strains of spontaneous Rorb mutant mice with a high-stepping gait phenotype. We show retinal abnormalities in a subset of these mutants and demonstrate significant differences in various behavioral phenotypes related to cognition. Gene expression analyses in all 5 mutants reveal a shared over-representation of the unfolded protein response and pathways related to endoplasmic reticulum stress, suggesting a possible mechanism of susceptibility relevant to patients.


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