A homozygous loss-of-function mutation in PDE2A associated to early-onset hereditary chorea

Vincenzo Salpietro, Belen Perez-Dueñas, Kosuke Nakashima, Victoria San Antonio-Arce, Andreea Manole, Stephanie Efthymiou, Jana Vandrovcova, Conceicao Bettencourt, Niccolò E. Mencacci, Christine Klein, Michy P. Kelly, Ceri H. Davies, Haruhide Kimura, Alfons Macaya, Henry Houlden*

*Corresponding author for this work
4 Citations (Scopus)


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’,5’-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.

Original languageEnglish
JournalMovement Disorders
Issue number3
Pages (from-to)482-488
Number of pages7
Publication statusPublished - 01.03.2018

Research Areas and Centers

  • Research Area: Medical Genetics


Dive into the research topics of 'A homozygous loss-of-function mutation in PDE2A associated to early-onset hereditary chorea'. Together they form a unique fingerprint.

Cite this