期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 98, 期 4, 页码 735-743出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2016.03.015
关键词
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资金
- Wellbeing of Women [RG992]
- University of Leeds Biomedical Health Research Centre [PSF42]
- Academy of Finland Research Council for Health [138566, 266498, 273790]
- Sigrid Juselius Foundation
- Finland Foundation for Pediatric Research
- Alma and K.A. Snellman Foundation
- Emil Aaltonen Foundation
- European Union [273669]
- Department of Pediatrics and Adolescence at Oulu University Hospital (Special State Grants for Health Research)
- Action Medical Research [1722] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1284, ICH1031] Funding Source: researchfish
- Medical Research Council [MC_U120097115, G0700995, MR/L01629X/1, MR/K02342X/1, 1116129] Funding Source: researchfish
- Rosetrees Trust [M576] Funding Source: researchfish
- MRC [MC_U120097115, G0700995, MR/L01629X/1, MR/K02342X/1] Funding Source: UKRI
- Academy of Finland (AKA) [273790, 266498, 138566, 266498, 138566, 273790] Funding Source: Academy of Finland (AKA)
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.
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