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

Abstract

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 (D1) 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 D1 agonist Chloro APB resulted in significantly reduced cyclic AMP levels. Numerous D1 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 D1 receptor in motor control.

Mechanisms of GNAL linked dystonia

“…Mutations in five genes (GCH1, TH, PTS, SPR, and QDPR) that lead to disruption of the synthesis of dopamine are causative for dystonia [24][25][26][27][28]. Also upstream of Gα olf , mutations in the D1 dopamine receptor (DRD1) are linked to infantile parkinsonism-dystonia and tardive-like dystonia [29,30]. Downstream of Gα olf , there are dystonia associated mutations in ADCY5, encoding adenylate cyclase 5, the enzyme responsible for the second messenger cAMP [31].…”