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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 763-771 |
| Number of pages | 9 |
| Journal | American journal of human genetics |
| Volume | 98 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 7 2016 |
Funding
We would like to extend our thanks to the individuals whose participation made this research possible. This work was supported financially by the Medical Research Council and Wellcome Trust (Strategic Award WT089698/Z/09/Z), the Netherlands Organization of Scientific Research (ZonMW grant 40-41200-98-9131), and grants from the Bachman-Strauss Dystonia Parkinsonism Foundation, National Institute for Health Research (NIHR) Bioresource Rare Diseases, and UK10K. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The work was undertaken at University College London (UCL) Hospitals, Great Ormond Street Hospital for Children NHS Foundation Trust, and UCL, which receive support from the Department of Health\u2019s NIHR Biomedical Research Center funding streams. We acknowledge the \u201CCell Lines and DNA Bank of Movement Disorders and Mitochondrial Diseases\u201D of the Telethon Network of Genetic Biobanks (grant GTB12001J) and the Eurobiobank Network, which provided the Italian samples. N.E.M. is funded by a NIHR funding scheme. A.M.P. is funded by the Reta Lila Weston Trust. M.A.K. is funded by a Wellcome Intermediate Fellowship. Next-generation sequencing was performed at the UCL Institute of Neurology Sequencing Facility and the Genome Technology Center at the Radboudumc. Expression data were provided by the UK Human Brain Expression Consortium (UKBEC), which comprises John A. Hardy, Mina Ryten, Michael Weale, Daniah Trabzuni, Adaikalavan Ramasamy, Colin Smith, and Robert Walker. UKBEC members are affiliated with the UCL Institute of Neurology (J.H., M.R., and D.T.), King\u2019s College London (M.R., M.W., and A.R.), and University of Edinburgh (C.S. and R.W.).
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)