Biallelic Mutations in PDE10A Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy

Christine P Diggle; Stacey J Sukoff Rizzo; Michael Popiolek; Reetta Hinttala; Jan-Philip Schülke; Manju A Kurian; Ian M Carr; Alexander F Markham; David T Bonthron; Christopher Watson; Saghira Malik Sharif; Veronica Reinhart; Larry C James; Michelle A Vanase-Frawley; Erik Charych; Melanie Allen; John Harms; Christopher J Schmidt; Joanne Ng; Karen Pysden; Christine Strick; Päivi Vieira; Katariina Mankinen; Hannaleena Kokkonen; Matti Kallioinen; Raija Sormunen; Juha O Rinne; Jarkko Johansson; Kati Alakurtti; Laura Huilaja; Tiina Hurskainen; Kaisa Tasanen; Eija Anttila; Tiago Reis Marques; Oliver Howes; Marius Politis; Somayyeh Fahiminiya; Khanh Q Nguyen; Jacek Majewski; Johanna Uusimaa; Eamonn Sheridan; Nicholas J Brandon

doi:10.1016/j.ajhg.2016.03.015

Biallelic Mutations in PDE10A Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy

Am J Hum Genet. 2016 Apr 7;98(4):735-43. doi: 10.1016/j.ajhg.2016.03.015.

Authors

Christine P Diggle¹, Stacey J Sukoff Rizzo², Michael Popiolek², Reetta Hinttala³, Jan-Philip Schülke², Manju A Kurian⁴, Ian M Carr¹, Alexander F Markham¹, David T Bonthron¹, Christopher Watson¹, Saghira Malik Sharif¹, Veronica Reinhart², Larry C James², Michelle A Vanase-Frawley⁵, Erik Charych², Melanie Allen⁵, John Harms², Christopher J Schmidt², Joanne Ng⁶, Karen Pysden⁷, Christine Strick², Päivi Vieira⁸, Katariina Mankinen⁹, Hannaleena Kokkonen¹⁰, Matti Kallioinen¹¹, Raija Sormunen¹², Juha O Rinne¹³, Jarkko Johansson¹⁴, Kati Alakurtti¹⁵, Laura Huilaja¹⁶, Tiina Hurskainen¹⁶, Kaisa Tasanen¹⁶, Eija Anttila⁸, Tiago Reis Marques¹⁷, Oliver Howes¹⁸, Marius Politis¹⁹, Somayyeh Fahiminiya²⁰, Khanh Q Nguyen²¹, Jacek Majewski²⁰, Johanna Uusimaa²², Eamonn Sheridan²³, Nicholas J Brandon²⁴

Affiliations

¹ School of Medicine, University of Leeds, Leeds LS9 7TF, UK.
² Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA.
³ 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.
⁴ Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK; Department of Neurology, Great Ormond Street Hospital, London WC1N 1EH, UK.
⁵ Pfizer Research and Development, Groton, CT 06340, USA.
⁶ Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK; Institute of Women's Health, University College London, London WC1N 1EH, UK.
⁷ Department of Pediatric Neurology, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK.
⁸ 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.
⁹ Länsi-Pohja Central Hospital, 94100 Kemi, Finland.
¹⁰ 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.
¹¹ Department of Pathology, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland.
¹² 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.
¹³ 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.
¹⁴ Turku PET Centre, Turku University Hospital and University of Turku, PO Box 52, 20521 Turku, Finland.
¹⁵ 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.
¹⁶ 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.
¹⁷ Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London SE5 8AF, UK.
¹⁸ 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.
¹⁹ Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London SE5 8AF, UK.
²⁰ Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Génome Québec Innovation Centre, Montreal, Quebec, QC H3A 0G1, Canada.
²¹ Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
²² 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.
²³ School of Medicine, University of Leeds, Leeds LS9 7TF, UK. Electronic address: e.sheridan@leeds.ac.uk.
²⁴ Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA. Electronic address: nick.brandon@azneuro.com.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Amino Acid Sequence
Animals
Corpus Striatum / pathology*
Disease Models, Animal
Gene Expression Regulation
Genetic Variation
HEK293 Cells
Humans
Hyperkinesis / diagnosis
Hyperkinesis / genetics*
Hyperkinesis / pathology
Male
Mice
Mice, Inbred BALB C
Molecular Sequence Data
Mutation*
Pedigree
Phosphodiesterase Inhibitors / metabolism
Phosphoric Diester Hydrolases / genetics*
Sequence Alignment

Substances

Phosphodiesterase Inhibitors
PDE10A protein, human
Pde10a protein, mouse
Phosphoric Diester Hydrolases

Abstract

Publication types

MeSH terms

Substances

Grants and funding