ArticleAmerican journal of human genetics2016
Biallelic Mutations in PDE10A Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy.
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Article in American journal of human genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
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37citing papers in PubMed, 1 pooled it
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Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it, 80 citations in OpenAlex.
- Decoding the Alphabet Soup: A Practical Guide to Genetic Testing in Hyperkinetic Movement Disorders.Tremor and other hyperkinetic movements (New York, N.Y.) · 2025Pooled it
- Cancer-related movement disorders: A scoping review and diagnostic approach.Neuro-oncology practice · 2025Review
- Molecular Imbalances Between Striosome and Matrix Compartments Characterize the Pathogenesis and Pathophysiology of Huntington's Disease Model Mouse.International journal of molecular sciences · 2025Article
- Early-Onset Movement Disorder Syndrome Caused by Biallelic Variants in PDE1B Encoding Phosphodiesterase 1B.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- Epigenetic mechanisms governing cell type specific somatic expansion and toxicity in Huntington's disease.bioRxiv : the preprint server for biology · 2025Article
- Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies.Movement disorders : official journal of the Movement Disorder Society · 2024Article
- KCTD1 regulation of Adenylyl cyclase type 5 adjusts striatal cAMP signaling.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Exploring the Genetic Landscape of Chorea in Infancy and Early Childhood: Implications for Diagnosis and Treatment.Current issues in molecular biology · 2024Review
- Article
- The Impact of Mmu17 Non-Hsa21 Orthologous Genes in the Ts65Dn Mouse Model of Down Syndrome: The Gold Standard Refuted.Biological psychiatry · 2023Article
- Identification and characterisation of de novo germline structural variants in two commercial pig lines using trio-based whole genome sequencing.BMC genomics · 2023Article
- Genetic Links to Episodic Movement Disorders: Current Insights.The application of clinical genetics · 2023Review
- The Genetic Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders.Movement disorders : official journal of the Movement Disorder Society · 2022Article
- Insights into the medicinal chemistry of heterocycles integrated with a pyrazolo[1,5-RSC medicinal chemistry · 2022Review
- A Glimpse of Molecular Biomarkers in Huntington's Disease.International journal of molecular sciences · 2022Review
- Members of the KCTD family are major regulators of cAMP signaling.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Motor, epileptic, and developmental phenotypes in genetic disorders affecting G protein coupled receptors-cAMP signaling.Frontiers in neurology · 2022Review
- The Emerging Role of Phosphodiesterases in Movement Disorders.Movement disorders : official journal of the Movement Disorder Society · 2021Review
- Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016.International journal of molecular sciences · 2021Review
- Emerging and converging molecular mechanisms in dystonia.Journal of neural transmission (Vienna, Austria : 1996) · 2021Review
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Authors and funding
42 authors at 13 institutions in 4 countries.
Christine P DiggleSchool of Medicine, University of Leeds, Leeds LS9 7TF, UK.
Stacey J Sukoff RizzoNeuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
Michael PopiolekNeuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
Reetta HinttalaPEDEGO 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.
Jan-Philip SchülkeNeuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
Manju A KurianDevelopmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK; Department of Neurology, Great Ormond Street Hospital, London WC1N 1EH, UK.
Ian M CarrSchool of Medicine, University of Leeds, Leeds LS9 7TF, UK.
Alexander F MarkhamSchool of Medicine, University of Leeds, Leeds LS9 7TF, UK.
David T BonthronSchool of Medicine, University of Leeds, Leeds LS9 7TF, UK.
Christopher WatsonSchool of Medicine, University of Leeds, Leeds LS9 7TF, UK.
Saghira Malik SharifSchool of Medicine, University of Leeds, Leeds LS9 7TF, UK.
Veronica ReinhartNeuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
Larry C JamesNeuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
Michelle A Vanase-FrawleyPfizer Research and Development, Groton, CT 06340, USA.
Erik CharychNeuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
Melanie AllenPfizer Research and Development, Groton, CT 06340, USA.
John HarmsNeuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
Christopher J SchmidtNeuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
Joanne NgDevelopmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK; Institute of Women's Health, University College London, London WC1N 1EH, UK.
Karen PysdenDepartment of Pediatric Neurology, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK.
Christine StrickNeuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
Päivi VieiraPEDEGO 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.
Katariina MankinenLänsi-Pohja Central Hospital, 94100 Kemi, Finland.
Hannaleena KokkonenDepartment 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.
Matti KallioinenDepartment of Pathology, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland.
Raija SormunenBiocenter 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.
Juha O RinneDivision 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.
Jarkko JohanssonTurku PET Centre, Turku University Hospital and University of Turku, PO Box 52, 20521 Turku, Finland.
Kati AlakurttiTurku 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.
Laura HuilajaPEDEGO 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.
Tiina HurskainenPEDEGO 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.
Kaisa TasanenPEDEGO 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.
Eija AnttilaPEDEGO 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.
Tiago Reis MarquesDepartment of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London SE5 8AF, UK.
Oliver HowesDepartment 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.
Marius PolitisNeurodegeneration Imaging Group, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London SE5 8AF, UK.
Somayyeh FahiminiyaDepartment of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Génome Québec Innovation Centre, Montreal, Quebec, QC H3A 0G1, Canada.
Khanh Q NguyenMontreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
Jacek MajewskiDepartment of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Génome Québec Innovation Centre, Montreal, Quebec, QC H3A 0G1, Canada.
Johanna UusimaaPEDEGO 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.
Eamonn SheridanSchool of Medicine, University of Leeds, Leeds LS9 7TF, UK. Electronic address: e.sheridan@leeds.ac.uk.
Nicholas J BrandonNeuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA. Electronic address: nick.brandon@azneuro.com.
Pfizer (United States) · USUniversity of Oulu · FIUniversity of Leeds · GBTurku University Hospital · FIKing's College London · GBMcGill University and Génome Québec Innovation Centre · CAOulu University Hospital · FIGreat Ormond Street Hospital · GBImperial College London · GBLänsi-Pohjan Sairaanhoitopiirin Kuntayhtymä · FILeeds General Infirmary · GBMontreal Neurological Institute and Hospital · CAUniversity College London · GB
Funding
Medical Research Council G0700995Medical Research Council MC_U120097115Medical Research Council MR/K02342X/1Medical Research Council MR/L01629X/1
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.
Indexed as
MutationAllelesAmino Acid SequenceAnimalsCorpus StriatumDisease Models, AnimalGene Expression RegulationGenetic VariationHEK293 CellsHumansHyperkinesisMaleMiceMice, Inbred BALB CMolecular Sequence DataPedigreePDE10A protein, humanPde10a protein, mousePhosphodiesterase InhibitorsPhosphoric Diester Hydrolases
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