Despite remarkable advances in human genomics, most rare disorders remain undiagnosed, mechanistically obscure, and without effective treatments. In this study, we establish DRD1, encoding the dopamine D1 receptor (D1R), as a monogenic cause of an infantile-onset dystonia syndrome, for which pharmacological responsiveness may vary depending on the underlying molecular mechanism. Across three unrelated families, eight affected individuals exhibited generalised dystonia, axial hypotonia, and cognitive impairment and carried homozygous pathogenic missense DRD1 variants. Live-cell biosensor assays revealed that patient-derived DRD1 variants disrupt receptor integrity through mechanistically diverse failures, such as trafficking deficits and impaired agonist-induced activation-ultimately converging on a collapse of D1R-mediated signalling. In line with standard clinical practice and informed by these mechanistic insights, we initiated a trial of levodopa/carbidopa in two individuals in the index family with a partial-loss-of-function variant, which was associated with improvement in voluntary motor function and cognitive engagement. Moreover, in live-cell assays, we demonstrated that Mevidalen-a selective DRD1-positive allosteric modulator currently in clinical development-substantially improved signaling in patient-derived mutants in vitro, supporting a potential future mechanism-aligned therapeutic avenue. To broaden the clinical implications of our findings, we performed a structural interpretation of DRD1 variation in 807,162 individuals and identified 29 rare predicted deleterious missense variants in heterozygous carriers. These variants clustered within evolutionarily conserved transmembrane domains and signaling motifs, providing a basis for pathogenicity assignment and variant prioritization in clinical and research settings. Building on these insights, we developed a structure-informed pharmacological experimental framework that stratifies DRD1 variants according to molecular dysfunction and matches them with mechanistically aligned therapeutic strategies-namely, orthosteric agonists, pharmacological chaperones, allosteric modulators, and readthrough compounds. This in vitro approach enabled functional rescue of otherwise intractable variants, suggesting a potentially actionable molecular architecture across diverse genotypes, which remains to be tested clinically. Together, these findings identify biallelic DRD1 variants as a cause of infantile dystonia and support the potential for mechanism-informed therapeutic exploration, while emphasizing that clinical responsiveness may vary across individuals. More broadly, our integrated genomics-structure-pharmacology framework provides a proof-of-concept approach to functionally stratify G protein-coupled receptor (GPCR) variants, exemplified here by DRD1, and prioritise testable, mechanism-based therapeutic hypotheses for future evaluation.
Kayhan et al. (Wed,) studied this question.