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

doi:10.1002/mds.27286

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

Institute of Neurogenetics

74 Citations (Scopus)

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’,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 language	English
Journal	Movement Disorders
Volume	33
Issue number	3
Pages (from-to)	482-488
Number of pages	7
ISSN	0885-3185
DOIs	https://doi.org/10.1002/mds.27286
Publication status	Published - 01.03.2018

Funding

Acknowledgments: 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.

Research Areas and Centers

Research Area: Medical Genetics

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/mds.27286

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Salpietro, V., Perez-Dueñas, B., Nakashima, K., San Antonio-Arce, V., Manole, A., Efthymiou, S., Vandrovcova, J., Bettencourt, C., Mencacci, N. E., Klein, C., Kelly, M. P., Davies, C. H., Kimura, H., Macaya, A., & Houlden, H. (2018). A homozygous loss-of-function mutation in PDE2A associated to early-onset hereditary chorea. Movement Disorders, 33(3), 482-488. https://doi.org/10.1002/mds.27286

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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.",

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",

year = "2018",

month = mar,

day = "1",

doi = "10.1002/mds.27286",

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Salpietro, V, Perez-Dueñas, B, Nakashima, K, San Antonio-Arce, V, Manole, A, Efthymiou, S, Vandrovcova, J, Bettencourt, C, Mencacci, NE, Klein, C, Kelly, MP, Davies, CH, Kimura, H, Macaya, A & Houlden, H 2018, 'A homozygous loss-of-function mutation in PDE2A associated to early-onset hereditary chorea', Movement Disorders, vol. 33, no. 3, pp. 482-488. https://doi.org/10.1002/mds.27286

TY - JOUR

T1 - A homozygous loss-of-function mutation in PDE2A associated to early-onset hereditary chorea

AU - Salpietro, Vincenzo

AU - Perez-Dueñas, Belen

AU - Nakashima, Kosuke

AU - San Antonio-Arce, Victoria

AU - Manole, Andreea

AU - Efthymiou, Stephanie

AU - Vandrovcova, Jana

AU - Bettencourt, Conceicao

AU - Mencacci, Niccolò E.

AU - Klein, Christine

AU - Kelly, Michy P.

AU - Davies, Ceri H.

AU - Kimura, Haruhide

AU - Macaya, Alfons

AU - Houlden, Henry

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85041332116

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DO - 10.1002/mds.27286

M3 - Journal articles

C2 - 29392776

AN - SCOPUS:85041332116

SN - 0885-3185

VL - 33

SP - 482

EP - 488

JO - Movement Disorders

JF - Movement Disorders

IS - 3

ER -

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

Abstract

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