De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions

Niccolò E. Mencacci, Erik Jan Kamsteeg, Kosuke Nakashima, Lea R'Bibo, David S. Lynch, Bettina Balint, Michèl A A P Willemsen, Matthew E. Adams, Sarah Wiethoff, Kazunori Suzuki, Ceri H. Davies, Joanne Ng, Esther Meyer, Liana Veneziano, Paola Giunti, Deborah Hughes, F. Lucy Raymond, Miryam Carecchio, Giovanna Zorzi, Nardo NardocciChiara Barzaghi, Barbara Garavaglia, Vincenzo Salpietro, John Hardy, Alan M. Pittman, Henry Houlden, Manju A. Kurian, Haruhide Kimura, Lisenka E L M Vissers, Nicholas W. Wood*, Kailash P. Bhatia

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)763-771
Number of pages9
JournalAmerican journal of human genetics
Issue number4
StatePublished - Apr 7 2016

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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