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@ARTICLE{Reid:600663,
      author       = {Reid, Kimberley M. and Steel, Dora and Nair, Sanjana and
                      Bhate, Sanjay and Biassoni, Lorenzo and Sudhakar, Sniya and
                      Heys, Michelle and Burke, Elizabeth and Kamsteeg, Erik-Jan
                      and Hameed, Biju and Zech, Michael and Mencacci, Niccolo E.
                      and Barwick, Katy and Topf, Maya and Kurian, Manju A.},
      title        = {{L}oss-of-{F}unction {V}ariants in {DRD}1 in {I}nfantile
                      {P}arkinsonism-{D}ystonia},
      journal      = {Cells},
      volume       = {12},
      number       = {7},
      issn         = {2073-4409},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {PUBDB-2023-08086},
      pages        = {1046},
      year         = {2023},
      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.},
      cin          = {CSSB-LIV/UKE-MT},
      ddc          = {570},
      cid          = {$I:(DE-H253)CSSB-LIV_UKE-MT-20220525$},
      pnm          = {899 - ohne Topic (POF4-899) / DFG project
                      G:(GEPRIS)458949627 - Ganzgenom- und
                      Transkriptomsequenzierung zur Identifizierung neuer
                      Krankheitsgene für Dystonie (458949627)},
      pid          = {G:(DE-HGF)POF4-899 / G:(GEPRIS)458949627},
      experiment   = {EXP:(DE-MLZ)NOSPEC-20140101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37048120},
      UT           = {WOS:000969745100001},
      doi          = {10.3390/cells12071046},
      url          = {https://bib-pubdb1.desy.de/record/600663},
}