ArticleAmerican journal of human genetics2016
De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions.
Article in American journal of human genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers, 1 of them a synthesis that pooled it.
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Who cites it
58 citing papers in PubMed, 1 synthesis or guideline pooled it, 117 citations in OpenAlex.
- Decoding the Alphabet Soup: A Practical Guide to Genetic Testing in Hyperkinetic Movement Disorders.Tremor and other hyperkinetic movements (New York, N.Y.) · 2025Pooled it
- Genomic structural variations distinguishing archaic and modern humans are associated with neurodevelopment.iScience · 2026Article
- Pathogenic variants in BORCS5 cause a spectrum of neurodevelopmental and neurodegenerative disorders with lysosomal dysfunction.The Journal of clinical investigation · 2026Article
- Expanding the repertoire of loss-of-function variants in HACE1 causing complex spastic paraplegia: literature review and recommendations on clinical management.Human genomics · 2026Review
- Elevated local field potential power characterizes choreic storms identified by deep brain stimulator event capture.Frontiers in neurology · 2026Article
- Inhibition of Phosphodiesterase 10A by MP-10 Rescues Behavioral Deficits and Normalizes Microglial Morphology and Synaptic Pruning in A Mouse Model of FOXP1 Syndrome.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Early-Onset Movement Disorder Syndrome Caused by Biallelic Variants in PDE1B Encoding Phosphodiesterase 1B.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- Bi-allelic KICS2 mutations impair KICSTOR complex-mediated mTORC1 regulation, causing intellectual disability and epilepsy.American journal of human genetics · 2025Article
- Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies.Movement disorders : official journal of the Movement Disorder Society · 2024Article
- KCTD1 regulation of Adenylyl cyclase type 5 adjusts striatal cAMP signaling.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- ZSCAN10 deficiency causes a neurodevelopmental disorder with characteristic oto-facial malformations.Brain : a journal of neurology · 2024Article
- Exploring the Genetic Landscape of Chorea in Infancy and Early Childhood: Implications for Diagnosis and Treatment.Current issues in molecular biology · 2024Review
- A rare inherited homozygous missense variant inTranslational pediatrics · 2024Article
- Genome Sequencing of Idiopathic Speech Delay.Human mutation · 2024Article
- Differential diagnosis of chorea (guidelines of the German Neurological Society).Neurological research and practice · 2023Article
- Article
- Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders.Nature communications · 2023Article
- The Impact of Mmu17 Non-Hsa21 Orthologous Genes in the Ts65Dn Mouse Model of Down Syndrome: The Gold Standard Refuted.Biological psychiatry · 2023Article
- Identification and characterisation of de novo germline structural variants in two commercial pig lines using trio-based whole genome sequencing.BMC genomics · 2023Article
- Childhood-Onset Choreo-Dystonia Due to a Recurrent Novel Homozygous NonsenseMovement disorders clinical practice · 2023Review
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Authors and funding
31 authors at 10 institutions in 6 countries.
Funding
Abstract
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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