De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions
Publication year
2016Author(s)
Source
American Journal of Human Genetics, 98, 4, (2016), pp. 763-71ISSN
Publication type
Article / Letter to editor
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Organization
Human Genetics
Paediatrics - OUD tm 2017
Neurology
Journal title
American Journal of Human Genetics
Volume
vol. 98
Issue
iss. 4
Page start
p. 763
Page end
p. 71
Subject
Radboudumc 12: Sensory disorders DCMN: Donders Center for Medical Neuroscience; Radboudumc 3: Disorders of movement DCMN: Donders Center for Medical Neuroscience; Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical NeuroscienceAbstract
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.
This item appears in the following Collection(s)
- Academic publications [246216]
- Electronic publications [133894]
- Faculty of Medical Sciences [93266]
- Open Access publications [107414]
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