Loss-of-Function Variants in DRD1 in Infantile Parkinsonism-Dystonia

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• The dopaminergic system is crucial for neurological functions, including voluntary movement control.
• Dopamine receptor D1 (DRD1) is the most abundant dopamine receptor in the central nervous system, highly expressed in the striatum.

Purpose of the Study:

• To investigate the genetic basis of severe infantile parkinsonism-dystonia with features of dopamine deficiency.
• To identify the causative gene and understand the functional consequences of the identified genetic variant.

Main Methods:

• Triome whole-genome sequencing was performed on a proband with infantile parkinsonism-dystonia.
• In vitro heterologous expression systems were used to determine the functional impact of the identified DRD1 variant.
• Structure-function modeling and in vitro assays assessed protein binding and signaling.

Main Results:

• A homozygous variant (c.110C>A, p.T37K) in the DRD1 gene was identified in the proband.
• The DRD1-T37K variant resulted in a loss of protein function, with reduced substrate binding and impaired cyclic AMP signaling.
• The patient showed no clinical improvement with dopaminergic therapy, consistent with the cellular defect.

Conclusions:

• DRD1 is identified as a novel disease-associated gene responsible for infantile parkinsonism-dystonia.
• This study underscores the critical role of the dopamine D1 receptor in motor control and neurodevelopment.
• The findings suggest that D1 receptor dysfunction can lead to severe neurological impairment.