Loss-of-Function Variants in <i>DRD1</i> in Infantile Parkinsonism-Dystonia
Kimberley M. Reid,
Dora Steel,
Sanjana Nair,
Sanjay Bhate,
Lorenzo Biassoni,
Sniya Sudhakar,
Michelle Heys,
Elizabeth Burke,
Erik-Jan Kamsteeg,
Genomics England Research Consortium,
Biju Hameed,
Michael Zech,
Niccolo E. Mencacci,
Katy Barwick,
Maya Topf,
Manju A. Kurian
Affiliations
Kimberley M. Reid
Molecular Neurosciences, Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL GOS Institute of Child Health, London WC1N 1DZ, UK
Dora Steel
Molecular Neurosciences, Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL GOS Institute of Child Health, London WC1N 1DZ, UK
Sanjana Nair
Leibniz Institute of Virology (LIV), Centre for Structural Systems Biology (CSSB), 20251 Hamburg, Germany
Sanjay Bhate
Department of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK
Lorenzo Biassoni
Department of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK
Sniya Sudhakar
Department of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK
Michelle Heys
Department of Population, Policy and Practice, UCL GOS Institute of Child Health, London WC1N 1DZ, UK
Elizabeth Burke
Office of the Clinical Director, National Human Genome Research Institute, Bethesda, MD 20892, USA
Erik-Jan Kamsteeg
Department of Human Genetics, Radboud University Medical Center, 6525 Nijmegen, The Netherlands
Genomics England Research Consortium
Genomics England, London EC1M 6BQ, UK
Biju Hameed
Department of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK
Michael Zech
Institute of Human Genetics, School of Medicine, Technical University of Munich, 85354 Munich, Germany
Niccolo E. Mencacci
Feinberg School of Medicine, Northwestern University, Chicago IL 60611, USA
Katy Barwick
Molecular Neurosciences, Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL GOS Institute of Child Health, London WC1N 1DZ, UK
Maya Topf
Leibniz Institute of Virology (LIV), Centre for Structural Systems Biology (CSSB), 20251 Hamburg, Germany
Manju A. Kurian
Molecular Neurosciences, Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL GOS Institute of Child Health, London WC1N 1DZ, UK
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.
