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

Genomics England Research Consortium

doi:10.3390/cells12071046

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

Genomics England Research Consortium

Neurology

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English (US)
Article number	1046
Journal	Cells
Volume	12
Issue number	7
DOIs	https://doi.org/10.3390/cells12071046
State	Published - Apr 2023

Funding

The authors would like to thank the participant and her family. Figures presented here were created with BioRender.com . This study made use of DECIPHER ( https://www.deciphergenomics.org accessed on 1 December 2022), which is funded by Wellcome. We thank the DDD study, which presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health was made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Maya Topf would like to thank Leibniz ScienceCampus InterACt, funded by the BWFGB Hamburg and the Leibniz Association. M.A.K., K.M.R. and D.S. are funded through a National Institute for Health Research Professorship for M.A.K (NIHR-RP-2016-07-019). M.A.K is also funded by Rosetrees Trust (CF2\\100018), the Sir Jules Thorn Trust (JTA-017) and the MRC (MR/S036784/1). M.Z. receives research support from the German Research Foundation (DFG 458949627; ZE 1213/2-1).

Keywords

dopamine
DRD1
dystonia
parkinsonism

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/cells12071046

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title = "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.",

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author = "{Genomics England Research Consortium} and Reid, {Kimberley M.} and Dora Steel and Sanjana Nair and Sanjay Bhate and Lorenzo Biassoni and Sniya Sudhakar and Michelle Heys and Elizabeth Burke and Kamsteeg, {Erik Jan} and Biju Hameed and Michael Zech and Mencacci, {Niccolo E.} and Katy Barwick and Maya Topf and Kurian, {Manju A.}",

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AU - Genomics England Research Consortium

AU - Reid, Kimberley M.

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AU - Nair, Sanjana

AU - Bhate, Sanjay

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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.

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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