title: Biallelic Mutations in PDE10A Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy.
abstract: Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species.
authors.affiliation: School of Medicine, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Christine P
authors.initials: CP
authors.lastname: Diggle
authors.affiliation: Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
authors.forename: Stacey J
authors.initials: SJ
authors.lastname: Sukoff Rizzo
authors.affiliation: Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Popiolek
authors.affiliation: PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, PO Box 23, 90029 Oulu, Finland; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada; Biocenter Oulu, University of Oulu, PO Box 5000, 90014 Oulu, Finland.
authors.forename: Reetta
authors.initials: R
authors.lastname: Hinttala
authors.affiliation: Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
authors.forename: Jan-Philip
authors.initials: JP
authors.lastname: Schülke
authors.affiliation: Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK; Department of Neurology, Great Ormond Street Hospital, London WC1N 1EH, UK.
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
authors.affiliation: School of Medicine, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.affiliation: School of Medicine, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Markham
authors.affiliation: School of Medicine, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: David T
authors.initials: DT
authors.lastname: Bonthron
authors.affiliation: School of Medicine, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Watson
authors.affiliation: School of Medicine, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Saghira Malik
authors.initials: SM
authors.lastname: Sharif
authors.affiliation: Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Reinhart
authors.affiliation: Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
authors.forename: Larry C
authors.initials: LC
authors.lastname: James
authors.affiliation: Pfizer Research and Development, Groton, CT 06340, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Vanase-Frawley
authors.affiliation: Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Charych
authors.affiliation: Pfizer Research and Development, Groton, CT 06340, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Allen
authors.affiliation: Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
authors.forename: John
authors.initials: J
authors.lastname: Harms
authors.affiliation: Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schmidt
authors.affiliation: Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK; Institute of Women's Health, University College London, London WC1N 1EH, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Ng
authors.affiliation: Department of Pediatric Neurology, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Pysden
authors.affiliation: Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Strick
authors.affiliation: PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, PO Box 23, 90029 Oulu, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Vieira
authors.affiliation: Länsi-Pohja Central Hospital, 94100 Kemi, Finland.
authors.forename: Katariina
authors.initials: K
authors.lastname: Mankinen
authors.affiliation: Department of Clinical Chemistry, University of Oulu, PO Box 5000, 90014, Oulu Finland; Northern Finland Laboratory Centre, Oulu University Hospital, PO Box 500, 90029 Oulu, Finland.
authors.forename: Hannaleena
authors.initials: H
authors.lastname: Kokkonen
authors.affiliation: Department of Pathology, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Kallioinen
authors.affiliation: Biocenter Oulu, University of Oulu, PO Box 5000, 90014 Oulu, Finland; Department of Pathology, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland.
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.affiliation: Division of Clinical Neurosciences, Turku University Hospital and University of Turku, PO Box 52, 20521 Turku, Finland; Turku PET Centre, Turku University Hospital and University of Turku, PO Box 52, 20521 Turku, Finland.
authors.forename: Juha O
authors.initials: JO
authors.lastname: Rinne
authors.affiliation: Turku PET Centre, Turku University Hospital and University of Turku, PO Box 52, 20521 Turku, Finland.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Johansson
authors.affiliation: Turku PET Centre, Turku University Hospital and University of Turku, PO Box 52, 20521 Turku, Finland; Department of Diagnostic Radiology, University of Turku and Turku University Hospital, PO Box 52, 20521 Turku, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Alakurtti
authors.affiliation: PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland; Department of Dermatology and Oulu Center for Cell-Matrix Research, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Huilaja
authors.affiliation: PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland; Department of Dermatology and Oulu Center for Cell-Matrix Research, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Hurskainen
authors.affiliation: PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland; Department of Dermatology and Oulu Center for Cell-Matrix Research, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Tasanen
authors.affiliation: PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, PO Box 23, 90029 Oulu, Finland.
authors.forename: Eija
authors.initials: E
authors.lastname: Anttila
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London SE5 8AF, UK.
authors.forename: Tiago Reis
authors.initials: TR
authors.lastname: Marques
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London SE5 8AF, UK; MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Howes
authors.affiliation: Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London SE5 8AF, UK.
authors.forename: Marius
authors.initials: M
authors.lastname: Politis
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Génome Québec Innovation Centre, Montreal, Quebec, QC H3A 0G1, Canada.
authors.forename: Somayyeh
authors.initials: S
authors.lastname: Fahiminiya
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
authors.forename: Khanh Q
authors.initials: KQ
authors.lastname: Nguyen
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Génome Québec Innovation Centre, Montreal, Quebec, QC H3A 0G1, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, PO Box 23, 90029 Oulu, Finland; Biocenter Oulu, University of Oulu, PO Box 5000, 90014 Oulu, Finland. Electronic address: johanna.uusimaa@oulu.fi.
authors.forename: Johanna
authors.initials: J
authors.lastname: Uusimaa
authors.affiliation: School of Medicine, University of Leeds, Leeds LS9 7TF, UK. Electronic address: e.sheridan@leeds.ac.uk.
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
authors.affiliation: Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA. Electronic address: nick.brandon@azneuro.com.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D006948:Hyperkinesis / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D010726:Phosphodiesterase Inhibitors; C119843:PDE10A protein, human; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases