title: De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions.
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.
authors.affiliation: 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.
authors.forename: Niccolò E
authors.initials: NE
authors.lastname: Mencacci
authors.affiliation: Department of Human Genetics, Donders Centre for Brain, Cognition, and Behavior, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Erik-Jan
authors.initials: EJ
authors.lastname: Kamsteeg
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 251-8555 Fujisawa, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Nakashima
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK.
authors.forename: Lea
authors.initials: L
authors.lastname: R'Bibo
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK.
authors.forename: David S
authors.initials: DS
authors.lastname: Lynch
authors.affiliation: 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.
authors.forename: Bettina
authors.initials: B
authors.lastname: Balint
authors.affiliation: Department of Paediatric Neurology, Donders Centre for Brain, Cognition, and Behavior, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Michèl A A P
authors.initials: MA
authors.lastname: Willemsen
authors.affiliation: Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, WC1N 3BG London, UK.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Adams
authors.affiliation: 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.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wiethoff
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 251-8555 Fujisawa, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 251-8555 Fujisawa, Japan.
authors.forename: Ceri H
authors.initials: CH
authors.lastname: Davies
authors.affiliation: Developmental Neurosciences, UCL Institute of Child Health, WC1N 1EH London, UK; Department of Neurology, Great Ormond Street Hospital, WC1N 3JH London, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Ng
authors.affiliation: Developmental Neurosciences, UCL Institute of Child Health, WC1N 1EH London, UK.
authors.forename: Esther
authors.initials: E
authors.lastname: Meyer
authors.affiliation: Institute of Translational Pharmacology, National Research Council, 00133 Rome, Italy.
authors.forename: Liana
authors.initials: L
authors.lastname: Veneziano
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Giunti
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Hughes
authors.affiliation: Department of Medical Genetics, University of Cambridge, CB2 0XY Cambridge, UK.
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
authors.affiliation: Neuropediatrics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; Molecular Neurogenetics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
authors.forename: Miryam
authors.initials: M
authors.lastname: Carecchio
authors.affiliation: Neuropediatrics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zorzi
authors.affiliation: Neuropediatrics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
authors.forename: Nardo
authors.initials: N
authors.lastname: Nardocci
authors.affiliation: Molecular Neurogenetics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Barzaghi
authors.affiliation: Molecular Neurogenetics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Garavaglia
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Salpietro
authors.affiliation: 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.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: 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.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Pittman
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: Developmental Neurosciences, UCL Institute of Child Health, WC1N 1EH London, UK; Department of Neurology, Great Ormond Street Hospital, WC1N 3JH London, UK.
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 251-8555 Fujisawa, Japan.
authors.forename: Haruhide
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Department of Human Genetics, Donders Centre for Brain, Cognition, and Behavior, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK. Electronic address: n.wood@ucl.ac.uk.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, WC1N 3BG London, UK.
authors.forename: Kailash P
authors.initials: KP
authors.lastname: Bhatia
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D002819:Chorea / Q000175:diagnosis / Q000235:genetics*; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D011487:Protein Conformation; D016415:Sequence Alignment; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D000242:Cyclic AMP; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP