TY  - JOUR
AU  - Reid, Kimberley M.
AU  - Steel, Dora
AU  - Nair, Sanjana
AU  - Bhate, Sanjay
AU  - Biassoni, Lorenzo
AU  - Sudhakar, Sniya
AU  - Heys, Michelle
AU  - Burke, Elizabeth
AU  - Kamsteeg, Erik-Jan
AU  - Hameed, Biju
AU  - Zech, Michael
AU  - Mencacci, Niccolo E.
AU  - Barwick, Katy
AU  - Topf, Maya
AU  - Kurian, Manju A.
TI  - Loss-of-Function Variants in DRD1 in Infantile Parkinsonism-Dystonia
JO  - Cells
VL  - 12
IS  - 7
SN  - 2073-4409
CY  - Basel
PB  - MDPI
M1  - PUBDB-2023-08086
SP  - 1046 
PY  - 2023
AB  - 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. 
LB  - PUB:(DE-HGF)16
C6  - pmid:37048120
UR  - <Go to ISI:>//WOS:000969745100001
DO  - DOI:10.3390/cells12071046
UR  - https://bib-pubdb1.desy.de/record/600663
ER  -