2. Academic Validation
  3. De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions

De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions

  • Am J Hum Genet. 2016 Apr 7;98(4):763-71. doi: 10.1016/j.ajhg.2016.02.015.
Niccolò E Mencacci 1,  Erik-Jan Kamsteeg 2,  Kosuke Nakashima 3,  Lea R'Bibo 4,  David S Lynch 4,  Bettina Balint 5,  Michèl A A P Willemsen 6,  Matthew E Adams 7,  Sarah Wiethoff 8,  Kazunori Suzuki 3,  Ceri H Davies 3,  Joanne Ng 9,  Esther Meyer 10,  Liana Veneziano 11,  Paola Giunti 4,  Deborah Hughes 4,  F Lucy Raymond 12,  Miryam Carecchio 13,  Giovanna Zorzi 14,  Nardo Nardocci 14,  Chiara Barzaghi 15,  Barbara Garavaglia 15,  Vincenzo Salpietro 4,  John Hardy 16,  Alan M Pittman 16,  Henry Houlden 4,  Manju A Kurian 9,  Haruhide Kimura 3,  Lisenka E L M Vissers 2,  Nicholas W Wood 17,  Kailash P Bhatia 18
Affiliations

Affiliations

  • 1 Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK; Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Department of Pathophysiology and Transplantation, Centro Dino Ferrari, Università degli Studi di Milano, 20149 Milan, Italy.
  • 2 Department of Human Genetics, Donders Centre for Brain, Cognition, and Behavior, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
  • 3 CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 251-8555 Fujisawa, Japan.
  • 4 Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK.
  • 5 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, WC1N 3BG London, UK; Department of Neurology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
  • 6 Department of Paediatric Neurology, Donders Centre for Brain, Cognition, and Behavior, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
  • 7 Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, WC1N 3BG London, UK.
  • 8 Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK; Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard Karls University, 72076 Tübingen, Germany.
  • 9 Developmental Neurosciences, UCL Institute of Child Health, WC1N 1EH London, UK; Department of Neurology, Great Ormond Street Hospital, WC1N 3JH London, UK.
  • 10 Developmental Neurosciences, UCL Institute of Child Health, WC1N 1EH London, UK.
  • 11 Institute of Translational Pharmacology, National Research Council, 00133 Rome, Italy.
  • 12 Department of Medical Genetics, University of Cambridge, CB2 0XY Cambridge, UK.
  • 13 Neuropediatrics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; Molecular Neurogenetics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
  • 14 Neuropediatrics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
  • 15 Molecular Neurogenetics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
  • 16 Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK; Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, WC1N 3BG London, UK.
  • 17 Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK. Electronic address: [email protected].
  • 18 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, WC1N 3BG London, UK.
PMID: 27058447 DOI: 10.1016/j.ajhg.2016.02.015
Abstract

Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C [p.Phe300Leu] in two individuals and c.1000T>C [p.Phe334Leu] in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions affect highly conserved Amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders.

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