DRD1-driven infantile dystonia: towards a mechanism-informed framework for GPCR receptoropathies - PubMed
8 hours ago
- #DRD1 dystonia
- #GPCR receptoropathies
- #mechanism-informed therapy
- DRD1, encoding dopamine D1 receptor (D1R), is identified as a monogenic cause of infantile-onset dystonia syndrome with symptoms like generalized dystonia, axial hypotonia, and cognitive impairment.
- Homozygous pathogenic missense DRD1 variants in affected individuals disrupt receptor function through diverse failures such as trafficking deficits and impaired activation, leading to collapsed D1R-mediated signaling.
- A trial of levodopa/carbidopa in individuals with partial-loss-of-function variants showed improved voluntary motor function and cognitive engagement, while the allosteric modulator Mevidalen enhanced signaling in patient-derived mutants in vitro.
- Analysis of DRD1 variants across a large cohort identified 29 rare predicted deleterious missense variants clustering in conserved regions, aiding pathogenicity assignment and variant prioritization.
- A structure-informed pharmacological framework stratifies DRD1 variants by molecular dysfunction and aligns them with therapeutic strategies like orthosteric agonists, pharmacological chaperones, allosteric modulators, and readthrough compounds.
- The integrated genomics-structure-pharmacology approach serves as a proof-of-concept for functionally stratifying GPCR variants and prioritizing mechanism-based therapies, emphasizing variable clinical responsiveness across individuals.