@article{20e14dba624949b2812b625578788602,
title = "A homozygous loss-of-function mutation in PDE2A associated to early-onset hereditary chorea",
abstract = "Background: We investigated a family that presented with an infantile-onset chorea-predominant movement disorder, negative for NKX2-1, ADCY5, and PDE10A mutations. Methods: Phenotypic characterization and trio whole-exome sequencing was carried out in the family. Results: We identified a homozygous mutation affecting the GAF-B domain of the 3{\textquoteright},5{\textquoteright}-cyclic nucleotide phosphodiesterase PDE2A gene (c.1439A>G; p.Asp480Gly) as the candidate novel genetic cause of chorea in the proband. PDE2A hydrolyzes cyclic adenosine/guanosine monophosphate and is highly expressed in striatal medium spiny neurons. We functionally characterized the p.Asp480Gly mutation and found that it severely decreases the enzymatic activity of PDE2A. In addition, we showed equivalent expression in human and mouse striatum of PDE2A and its homolog gene, PDE10A. Conclusions: We identified a loss-of-function homozygous mutation in PDE2A associated to early-onset chorea. Our findings possibly strengthen the role of cyclic adenosine monophosphate and cyclic guanosine monophosphate metabolism in striatal medium spiny neurons as a crucial pathophysiological mechanism in hyperkinetic movement disorders.",
keywords = "PDE2A, chorea, movement disorders, phosphodiesterase, striatum",
author = "Vincenzo Salpietro and Belen Perez-Due{\~n}as and Kosuke Nakashima and {San Antonio-Arce}, Victoria and Andreea Manole and Stephanie Efthymiou and Jana Vandrovcova and Conceicao Bettencourt and Mencacci, {Niccol{\`o} E.} and Christine Klein and Kelly, {Michy P.} and Davies, {Ceri H.} and Haruhide Kimura and Alfons Macaya and Henry Houlden",
note = "Funding Information: This study was supported by the Wellcome Trust (WT093205MA, WT104033AIA), Medical Research Council (to V.S. and H.H.), European Community's Seventh Framework Programme (FP7/2007-2013, under grant agreement No. 2012-305121; to H.H.), and National Institute for Health Research University College London Hospitals Biomedical Research Centre (to H.H.). M.P.K. is a recipient of an award from NIMH 1R01MH101130. C.K. is the recipient of a career development award from the Hermann and Lilly Schilling Foundation. The authors acknowledge Masaaki Nishimura for constructing the plasmids carrying genes of wild-type PDE2A and a mutant, c.1439A>G; p.(Asp480Gly). The authors acknowledge the individuals (and their family) who donated their brain to the Stanley Foundation and the Stanley Foundation for sharing this donation with our laboratory. Funding Information: Acknowledgments: This study was supported by the Wellcome Trust (WT093205MA, WT104033AIA), Medical Research Council (to V.S. and H.H.), European Community{\textquoteright}s Seventh Framework Programme (FP7/2007-2013, under grant agreement No. 2012-305121; to H.H.), and National Institute for Health Research University College London Hospitals Biomedical Research Centre (to H.H.). M.P.K. is a recipient of an award from NIMH 1R01MH101130. C.K. is the recipient of a career development award from the Hermann and Lilly Schilling Foundation. The authors acknowledge Masaaki Nishimura for constructing the plasmids carrying genes of wild-type PDE2A and a mutant, c.1439A>G; p.(Asp480Gly). The authors acknowledge the individuals (and their family) who donated their brain to the Stanley Foundation and the Stanley Foundation for sharing this donation with our laboratory. Publisher Copyright: {\textcopyright} 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.",
year = "2018",
month = mar,
doi = "10.1002/mds.27286",
language = "English (US)",
volume = "33",
pages = "482--488",
journal = "Movement Disorders",
issn = "0885-3185",
publisher = "John Wiley & Sons Inc.",
number = "3",
}