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

卷:12

Article

关键词: PROTEIN-COUPLED RECEPTORS;    DOPAMINE TRANSPORTER;    NEURONS;    EXPRESSION;    DISORDERS;    MUTATIONS;   

DOI  :  10.3390/cells12071046

来源: SCIE

【 摘 要 】

The human dopaminergic system is vital for a broad range of neurological processes, including the control of voluntary movement. Here we report a proband presenting with clinical features of dopamine deficiency: severe infantile parkinsonism-dystonia, characterised by frequent oculogyric crises, dysautonomia and global neurodevelopmental impairment. CSF neurotransmitter analysis was unexpectedly normal. Triome whole-genome sequencing revealed a homozygous variant (c.110C>A, (p.T37K)) in DRD1, encoding the most abundant dopamine receptor (D-1) in the central nervous system, most highly expressed in the striatum. This variant was absent from gnomAD, with a CADD score of 27.5. Using an in vitro heterologous expression system, we determined that DRD1-T37K results in loss of protein function. Structure-function modelling studies predicted reduced substrate binding, which was confirmed in vitro. Exposure of mutant protein to the selective D-1 agonist Chloro APB resulted in significantly reduced cyclic AMP levels. Numerous D-1 agonists failed to rescue the cellular defect, reflected clinically in the patient, who had no benefit from dopaminergic therapy. Our study identifies DRD1 as a new disease-associated gene, suggesting a crucial role for the D-1 receptor in motor control.