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Reid, K.M.* ; Steel, D.* ; Nair, S.* ; Bhate, S.* ; Biassoni, L.* ; Sudhakar, S.* ; Heys, M.* ; Burke, E.* ; Kamsteeg, E.J.* ; Hameed, B.* ; Zech, M. ; Mencacci, N.E.* ; Barwick, K.* ; Topf, M.* ; Kurian, M.A.*

Loss-of-function variants in DRD1 in infantile parkinsonism-dystonia.

Cells 12:15 (2023)
DOI PMC
Creative Commons Lizenzvertrag
Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Drd1 ; Dopamine ; Dystonia ; Parkinsonism; Protein-coupled Receptors; Dopamine Transporter; Neurons; Expression; Disorders; Mutations
ISSN (print) / ISBN 2073-4409
e-ISSN 2073-4409
Journal Cells
Quellenangaben Volume: 12, Issue: 7, Pages: , Article Number: 15 Supplement: ,
Publisher MDPI
Publishing Place Basel
Non-patent literature Publications
Institute(s) Institute of Neurogenomics (ING)
Grants German Research Foundation (DFG)
MRC
Sir Jules Thorn Trust
Rosetrees Trust
National Institute for Health Research Professorship