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 PysdenChristine 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

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)735-743
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - 7 Apr 2016


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