Mutations in the RAR-beta protein lead to MCOPS12 with pleiotropic defects of an unknown cause. The mutations in RAR-beta most likely result in conformational changes of the receptor’s ligand binding domain, hence to altered ligand binding and transcriptional activity of the receptor. These could be loss of function, reduction in function, or gain of normal function.
Figure 1: RAR-beta Protein
Movement disorders are typically explained by some dysfunction in the striatum, which forms a critical part of the motor control system in the brain. Information input comes from the hindbrain by dopaminergic neurons, which connect to medium spiny neurons (MSN) in the striatum. The striatum contains two distinct types of MSNs (D1R and D2R) that carry information to different brain regions. Both D1R and D2R are dopamine receptors.
RAR-beta is a transcription factor and the D2R dopamine receptor is one of its targets. It is hypothesized that changes in RAR-beta transcriptional activity change MSN gene expression, protein composition, and metabolic activity thus leading to the observed neurological disorders.
The RAinRARE consortium federates research teams from four academic institutions (see Figure 2) to establish disease models and determine the mechanism through which mutant forms of RAR-beta affect striatum functions. Ultimately, the consortium aims to develop therapeutic approaches for MCOPS12 and robust biomarkers for monitoring the efficiency of these approaches. The teams have obtained funding by the European Union via the E-Rare platform to support this research program.
- behavioral and histological analyses of RARB transgenic mouse models (having a single-point mutation equivalent to c.1159C>T (p.R387C) in human patients)
- functional genomic, metabolomic and proteomic analyses of transgenic mouse striatum
- generation of patient iPSC derived striatal neurons and their transcriptomic, proteomic and morphological analysis
- Establishment of an integrated knowledgebase with Findable, Accessible, Interoperable and Re-usable (FAIR) research data and identification of biomarkers