Biallelic Mutations in PDE1 0A Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy

被引：63

作者：

Diggle, Christine P. ^{[1
]}

Rizzo, Stacey J. Sukoff ^{[2
]}

Popiolek, Michael ^{[2
]}

Hinttala, Reetta ^{[3
,4
,5
,6
,7
,8
,9
]}

Schuelke, Jan-Philip ^{[2
]}

Kurian, Manju A. ^{[10
,11
]}

Carr, Ian M. ^{[1
]}

Markham, Alexander F. ^{[1
]}

Bonthron, David T. ^{[1
]}

Watson, Christopher ^{[1
]}

Sharif, Saghira Malik ^{[1
]}

Reinhart, Veronica ^{[2
]}

James, Larry C. ^{[2
]}

Vanase-Frawley, Michelle A. ^{[12
]}

Charych, Erik ^{[2
]}

Allen, Melanie ^{[12
]}

Harms, John ^{[2
]}

Schmidt, Christopher J. ^{[2
]}

Ng, Joanne ^{[10
,13
]}

Pysden, Karen ^{[14
]}

Strick, Christine ^{[2
]}

Vieira, Paeivi ^{[3
,4
,5
,6
]}

Mankinen, Katariina ^{[15
]}

Kokkonen, Hannaleena ^{[16
,17
]}

Kallioinen, Matti ^{[18
,19
]}

Sormunen, Raija ^{[9
,18
,19
]}

Rinne, Juha O. ^{[20
,21
,22
]}

Johansson, Jarkko ^{[21
,22
]}

Alakurtti, Kati ^{[21
,22
,23
,24
]}

Huilaja, Laura ^{[3
,4
,5
,19
,25
,26
]}

Hurskainen, Tiina ^{[3
,4
,5
,19
,25
,26
]}

Tasanen, Kaisa ^{[3
,4
,5
,19
,25
,26
]}

Anttila, Eija ^{[3
,4
,5
,6
]}

Marques, Tiago Reis ^{[27
]}

Howes, Oliver ^{[27
,28
]}

Politis, Marius ^{[29
]}

Fahiminiya, Somayyeh ^{[7
,30
,31
]}

Nguyen, Khanh Q. ^{[8
]}

Majewski, Jacek ^{[7
,30
,31
]}

Uusimaa, Johanna ^{[3
,4
,5
,6
,9
]}

Sheridan, Eamonn ^{[1
,9
]}

Brandon, Nicholas J. ^{[2
,32
]}

机构：

[1] Univ Leeds, Sch Med, Leeds LS9 7TF, W Yorkshire, England

[2] Pfizer Res & Dev, Neurosci Res Unit, Cambridge, MA 02139 USA

[3] Univ Oulu, PEDEGO Res Unit, Oulu 90014, Finland

[4] Univ Oulu, Med Res Ctr Oulu, Oulu 90014, Finland

[5] Oulu Univ Hosp, POB 5000, Oulu 90014, Finland

[6] Oulu Univ Hosp, Dept Children & Adolescents, POB 23, Oulu 90029, Finland

[7] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada

[8] McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada

[9] Univ Oulu, Bioctr Oulu, POB 5000, Oulu 90014, Finland

[10] UCL Inst Child Hlth, Dev Neurosci Programme, London WC1N 1EH, England

[11] Great Ormond St Hosp Sick Children, Dept Neurol, London WC1N 1EH, England

[12] Pfizer Res & Dev, Groton, CT 06340 USA

[13] UCL, Inst Womens Hlth, London WC1N 1EH, England

[14] Leeds Gen Infirm, Dept Pediat Neurol, Great George St, Leeds LS1 3EX, W Yorkshire, England

[15] Lansi Pohja Cent Hosp, Kemi 94100, Finland

[16] Univ Oulu, Dept Clin Chem, POB 5000, Oulu 90014, Finland

[17] Oulu Univ Hosp, Northern Finland Lab Ctr, POB 500, Oulu 90029, Finland

[18] Oulu Univ Hosp, Dept Pathol, Oulu 90014, Finland

[19] Univ Oulu, POB 5000, Oulu 90014, Finland

[20] Turku Univ Hosp, Div Clin Neurosci, Turku 20521, Finland

[21] Univ Turku, POB 52, Turku 20521, Finland

[22] Turku Univ Hosp, Turku PET Ctr, Turku 20521, Finland

[23] Univ Turku, Dept Diagnost Radiol, Turku 20521, Finland

[24] Turku Univ Hosp, POB 52, Turku 20521, Finland

[25] Oulu Univ Hosp, Dept Dermatol, Oulu 90014, Finland

[26] Oulu Univ Hosp, Oulu Ctr Cell Matrix Res, Oulu 90014, Finland

[27] Kings Coll London, Dept Psychosis Studies, Inst Psychiat Psychol & Neurosci, London SE5 8AF, England

[28] Univ London Imperial Coll Sci Technol & Med, MRC Clin Sci Ctr, Hammersmith Hosp Campus, London W12 0NN, England

[29] Kings Coll London, Neurodegenerat Imaging Grp, Inst Psychiat Psychol & Neurosci, London SE5 8AF, England

[30] McGill Univ, Montreal, PQ H3A 0G1, Canada

[31] Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada

[32] AstraZeneca Neurosci, Innovat Medicines & Early Dev Biotech Unit, 141 Portland St, Cambridge, MA 02139 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2016年 / 98卷 / 04期

基金：

芬兰科学院;

关键词：

DNA-SEQUENCING DATA; HUNTINGTONS-DISEASE; PHOSPHODIESTERASE; 10A; IMMUNOHISTOCHEMICAL LOCALIZATION; PARKINSONS-DISEASE; MICE; SCHIZOPHRENIA; DYSKINESIA; FRAMEWORK; MODEL;

D O I：

10.1016/j.ajhg.2016.03.015

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species.

引用

页码：735 / 743

页数：9

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