DRD1-driven infantile dystonia: towards a mechanism-informed framework for GPCR receptoropathies

Area of Science:

• Genetics
• Neuroscience
• Pharmacology

Background:

• Most rare genetic disorders lack diagnoses and treatments.
• The dopamine D1 receptor (DRD1) plays a crucial role in neurological functions.

Purpose of the Study:

• To identify the genetic cause of an infantile-onset dystonia syndrome.
• To explore mechanism-aligned therapeutic strategies for DRD1-related disorders.

Main Methods:

• Whole-exome sequencing and segregation analysis in affected families.
• Live-cell biosensor assays to assess patient-derived DRD1 variant function.
• Structural interpretation of DRD1 variation in a large population cohort.
• Development of a structure-informed pharmacological framework for variant stratification.

Main Results:

• Homozygous pathogenic DRD1 missense variants were identified in eight individuals with infantile dystonia, hypotonia, and cognitive impairment.
• Patient-derived DRD1 variants exhibited diverse molecular defects, including impaired trafficking and activation, leading to signaling collapse.
• Levodopa/carbidopa showed partial improvement in motor function and cognition in two individuals.
• A selective DRD1 positive allosteric modulator (Mevidalen) rescued signaling in vitro.
• A framework was developed to stratify DRD1 variants and match them with potential therapies.

Conclusions:

• Biallelic DRD1 variants are a monogenic cause of infantile dystonia syndrome.
• Mechanism-informed therapeutic strategies, including agonists and allosteric modulators, show promise.
• An integrated genomics-structure-pharmacology approach can guide personalized treatment for GPCR-related disorders.