Relevance to Autism

A de novo missense variant in the RORB gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while two de novo likely-gene disruptive variants in this gene were observed in ASD probands from the Autism Sequencing Consortium (Satterstrom et al., 2020). Subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in Satterstrom et al., 2020 identified RORB as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified RORB as a gene reaching exome-wide significance (P < 2.5E-06). Mutations in the RORB gene are responsible for susceptibility to idiopathic generalized epilepsy-15 (EIG15; OMIM 618357); Rudolf et al., 2016 found that two individuals from a cohort of patients with RORB-associated epilepsy also presented with autism spectrum disorder. Boudry-Labis et al., 2013 had previously shown that RORB was one of four genes within the minimal region of overlap in 9q21.13 microdeletion syndrome, a disorder characterized by developmental delay, epilepsy, behavioral abnormalities (including autistic features), and dysmorphic features. Rorb-knockout mice were found to display motor, olfactory, behavioral, and circadian phenotypes (Masana et al., 2007).

Molecular Function

The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. It is a DNA-binding protein that can bind as a monomer or as a homodimer to hormone response elements upstream of several genes to enhance the expression of those genes. The encoded protein has been shown to interact with NM23-2, a nucleoside diphosphate kinase involved in organogenesis and differentiation, and to help regulate the expression of some genes involved in circadian rhythm.

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Model Summary

Rorb is expressed by a population of spinal cord interneurons that mediate axodendritic/axosomatic feedforward inhibition of spinal projection neurons in the deep dorsal horn. Mice with a pathogenic mutation arising at the Rorb locus show an increased sensorimotor response in tactile PPI, in which an air puff stimulus precedes a loud acoustic tone. Rorb mutants, however, did not show any other ASD-like phenotypes. Specifically, Rorb mutants show normal startle response to a tactile stimulus, no anxiety phenotype, no hyperlocomotion and no sociability deficits.

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