Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 98, Issue 4, Pages 763-771Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2016.02.015
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Categories
Funding
- Medical Research Council and Wellcome Trust [WT089698/Z/09/Z]
- Netherlands Organization of Scientific Research (ZonMW) [40-41200-98-9131]
- Bachman-Strauss Dystonia Parkinsonism Foundation
- National Institute for Health Research (NIHR) Bioresource Rare Diseases
- Cell Lines and DNA Bank of Movement Disorders and Mitochondrial Diseases of the Telethon Network of Genetic Biobanks [GTB12001J]
- NIHR
- Reta Lila Weston Trust
- Wellcome Intermediate Fellowship
- [UK10K]
- Action Medical Research [1722] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [ICH1031, V1284] Funding Source: researchfish
- Medical Research Council [G0802760, G1001253, MR/J004758/1, G108/638, MR/K02342X/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0515-10082, NF-SI-0507-10376, NF-SI-0513-10064] Funding Source: researchfish
- Parkinson's UK [G-1107] Funding Source: researchfish
- Rosetrees Trust [M576] Funding Source: researchfish
- MRC [MR/K02342X/1, G108/638, G1001253, MR/J004758/1, G0802760] Funding Source: UKRI
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Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C [p.Phe300Leu] in two individuals and c.1000T>C [p.Phe334Leu] in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions affect highly conserved amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders.
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