PuSH - Publication Server of Helmholtz Zentrum München: Loss-of-function variants in <em>DRD1</em> in infantile parkinsonism-dystonia.

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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)

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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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