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

• Published in: American journal of human genetics Vol. 98; no. 4; pp. 735 - 743
• Main Authors: Diggle, Christine P., Sukoff Rizzo, Stacey J., Popiolek, Michael, Hinttala, Reetta, Schülke, Jan-Philip, Kurian, Manju A., Carr, Ian M., Markham, Alexander F., Bonthron, David T., Watson, Christopher, Sharif, Saghira Malik, Reinhart, Veronica, James, Larry C., Vanase-Frawley, Michelle A., Charych, Erik, Allen, Melanie, Harms, John, Schmidt, Christopher J., Ng, Joanne, Pysden, Karen, Strick, Christine, Vieira, Päivi, Mankinen, Katariina, Kokkonen, Hannaleena, Kallioinen, Matti, Sormunen, Raija, Rinne, Juha O., Johansson, Jarkko, Alakurtti, Kati, Huilaja, Laura, Hurskainen, Tiina, Tasanen, Kaisa, Anttila, Eija, Marques, Tiago Reis, Howes, Oliver, Politis, Marius, Fahiminiya, Somayyeh, Nguyen, Khanh Q., Majewski, Jacek, Uusimaa, Johanna, Sheridan, Eamonn, Brandon, Nicholas J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-04-2016; Cell Press; Elsevier
• Subjects: Alleles; Amino Acid Sequence; Animals; Babies; Corpus Striatum - pathology; Disease Models, Animal; Gene Expression Regulation; Genetic Variation; HEK293 Cells; Humans; Hyperkinesis - diagnosis; Hyperkinesis - genetics; Hyperkinesis - pathology; Kinetics; Ligands; Male; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Movement; Mutation; Pedigree; Phosphodiesterase Inhibitors - metabolism; Phosphoric Diester Hydrolases - genetics; Rodents; Sequence Alignment
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2016.03.015

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.