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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Biallelic Mutations in <italic>PDE10A</italic> Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy</title><author><name sortKey="Diggle, Christine P" sort="Diggle, Christine P" uniqKey="Diggle C" first="Christine P." last="Diggle">Christine P. Diggle</name><affiliation><nlm:aff id="aff1">School of Medicine, University of Leeds, Leeds LS9 7TF, UK</nlm:aff></affiliation></author><author><name sortKey="Sukoff Rizzo, Stacey J" sort="Sukoff Rizzo, Stacey J" uniqKey="Sukoff Rizzo S" first="Stacey J." last="Sukoff Rizzo">Stacey J. Sukoff Rizzo</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="Popiolek, Michael" sort="Popiolek, Michael" uniqKey="Popiolek M" first="Michael" last="Popiolek">Michael Popiolek</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="Hinttala, Reetta" sort="Hinttala, Reetta" uniqKey="Hinttala R" first="Reetta" last="Hinttala">Reetta Hinttala</name><affiliation><nlm:aff id="aff3">PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Children and Adolescents, Oulu University Hospital, PO Box 23, 90029 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Biocenter Oulu, University of Oulu, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Schulke, Jan Philip" sort="Schulke, Jan Philip" uniqKey="Schulke J" first="Jan-Philip" last="Schülke">Jan-Philip Schülke</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="Kurian, Manju A" sort="Kurian, Manju A" uniqKey="Kurian M" first="Manju A." last="Kurian">Manju A. Kurian</name><affiliation><nlm:aff id="aff8">Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff9">Department of Neurology, Great Ormond Street Hospital, London WC1N 1EH, UK</nlm:aff></affiliation></author><author><name sortKey="Carr, Ian M" sort="Carr, Ian M" uniqKey="Carr I" first="Ian M." last="Carr">Ian M. Carr</name><affiliation><nlm:aff id="aff1">School of Medicine, University of Leeds, Leeds LS9 7TF, UK</nlm:aff></affiliation></author><author><name sortKey="Markham, Alexander F" sort="Markham, Alexander F" uniqKey="Markham A" first="Alexander F." last="Markham">Alexander F. Markham</name><affiliation><nlm:aff id="aff1">School of Medicine, University of Leeds, Leeds LS9 7TF, UK</nlm:aff></affiliation></author><author><name sortKey="Bonthron, David T" sort="Bonthron, David T" uniqKey="Bonthron D" first="David T." last="Bonthron">David T. Bonthron</name><affiliation><nlm:aff id="aff1">School of Medicine, University of Leeds, Leeds LS9 7TF, UK</nlm:aff></affiliation></author><author><name sortKey="Watson, Christopher" sort="Watson, Christopher" uniqKey="Watson C" first="Christopher" last="Watson">Christopher Watson</name><affiliation><nlm:aff id="aff1">School of Medicine, University of Leeds, Leeds LS9 7TF, UK</nlm:aff></affiliation></author><author><name sortKey="Sharif, Saghira Malik" sort="Sharif, Saghira Malik" uniqKey="Sharif S" first="Saghira Malik" last="Sharif">Saghira Malik Sharif</name><affiliation><nlm:aff id="aff1">School of Medicine, University of Leeds, Leeds LS9 7TF, UK</nlm:aff></affiliation></author><author><name sortKey="Reinhart, Veronica" sort="Reinhart, Veronica" uniqKey="Reinhart V" first="Veronica" last="Reinhart">Veronica Reinhart</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="James, Larry C" sort="James, Larry C" uniqKey="James L" first="Larry C." last="James">Larry C. James</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="Vanase Frawley, Michelle A" sort="Vanase Frawley, Michelle A" uniqKey="Vanase Frawley M" first="Michelle A." last="Vanase-Frawley">Michelle A. Vanase-Frawley</name><affiliation><nlm:aff id="aff10">Pfizer Research and Development, Groton, CT 06340, USA</nlm:aff></affiliation></author><author><name sortKey="Charych, Erik" sort="Charych, Erik" uniqKey="Charych E" first="Erik" last="Charych">Erik Charych</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="Allen, Melanie" sort="Allen, Melanie" uniqKey="Allen M" first="Melanie" last="Allen">Melanie Allen</name><affiliation><nlm:aff id="aff10">Pfizer Research and Development, Groton, CT 06340, USA</nlm:aff></affiliation></author><author><name sortKey="Harms, John" sort="Harms, John" uniqKey="Harms J" first="John" last="Harms">John Harms</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="Schmidt, Christopher J" sort="Schmidt, Christopher J" uniqKey="Schmidt C" first="Christopher J." last="Schmidt">Christopher J. Schmidt</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="Ng, Joanne" sort="Ng, Joanne" uniqKey="Ng J" first="Joanne" last="Ng">Joanne Ng</name><affiliation><nlm:aff id="aff8">Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">Institute of Women’s Health, University College London, London WC1N 1EH, UK</nlm:aff></affiliation></author><author><name sortKey="Pysden, Karen" sort="Pysden, Karen" uniqKey="Pysden K" first="Karen" last="Pysden">Karen Pysden</name><affiliation><nlm:aff id="aff12">Department of Pediatric Neurology, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK</nlm:aff></affiliation></author><author><name sortKey="Strick, Christine" sort="Strick, Christine" uniqKey="Strick C" first="Christine" last="Strick">Christine Strick</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="Vieira, P Ivi" sort="Vieira, P Ivi" uniqKey="Vieira P" first="P Ivi" last="Vieira">P Ivi Vieira</name><affiliation><nlm:aff id="aff3">PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Children and Adolescents, Oulu University Hospital, PO Box 23, 90029 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Mankinen, Katariina" sort="Mankinen, Katariina" uniqKey="Mankinen K" first="Katariina" last="Mankinen">Katariina Mankinen</name><affiliation><nlm:aff id="aff13">Länsi-Pohja Central Hospital, 94100 Kemi, Finland</nlm:aff></affiliation></author><author><name sortKey="Kokkonen, Hannaleena" sort="Kokkonen, Hannaleena" uniqKey="Kokkonen H" first="Hannaleena" last="Kokkonen">Hannaleena Kokkonen</name><affiliation><nlm:aff id="aff14">Department of Clinical Chemistry, University of Oulu, PO Box 5000, 90014, Oulu Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff15">Northern Finland Laboratory Centre, Oulu University Hospital, PO Box 500, 90029 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Kallioinen, Matti" sort="Kallioinen, Matti" uniqKey="Kallioinen M" first="Matti" last="Kallioinen">Matti Kallioinen</name><affiliation><nlm:aff id="aff16">Department of Pathology, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Sormunen, Raija" sort="Sormunen, Raija" uniqKey="Sormunen R" first="Raija" last="Sormunen">Raija Sormunen</name><affiliation><nlm:aff id="aff7">Biocenter Oulu, University of Oulu, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff16">Department of Pathology, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Rinne, Juha O" sort="Rinne, Juha O" uniqKey="Rinne J" first="Juha O." last="Rinne">Juha O. Rinne</name><affiliation><nlm:aff id="aff17">Division of Clinical Neurosciences, Turku University Hospital and University of Turku, PO Box 52, 20521 Turku, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff18">Turku PET Centre, Turku University Hospital and University of Turku, PO Box 52, 20521 Turku, Finland</nlm:aff></affiliation></author><author><name sortKey="Johansson, Jarkko" sort="Johansson, Jarkko" uniqKey="Johansson J" first="Jarkko" last="Johansson">Jarkko Johansson</name><affiliation><nlm:aff id="aff18">Turku PET Centre, Turku University Hospital and University of Turku, PO Box 52, 20521 Turku, Finland</nlm:aff></affiliation></author><author><name sortKey="Alakurtti, Kati" sort="Alakurtti, Kati" uniqKey="Alakurtti K" first="Kati" last="Alakurtti">Kati Alakurtti</name><affiliation><nlm:aff id="aff18">Turku PET Centre, Turku University Hospital and University of Turku, PO Box 52, 20521 Turku, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff19">Department of Diagnostic Radiology, University of Turku and Turku University Hospital, PO Box 52, 20521 Turku, Finland</nlm:aff></affiliation></author><author><name sortKey="Huilaja, Laura" sort="Huilaja, Laura" uniqKey="Huilaja L" first="Laura" last="Huilaja">Laura Huilaja</name><affiliation><nlm:aff id="aff3">PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff20">Department of Dermatology and Oulu Center for Cell-Matrix Research, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Hurskainen, Tiina" sort="Hurskainen, Tiina" uniqKey="Hurskainen T" first="Tiina" last="Hurskainen">Tiina Hurskainen</name><affiliation><nlm:aff id="aff3">PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff20">Department of Dermatology and Oulu Center for Cell-Matrix Research, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Tasanen, Kaisa" sort="Tasanen, Kaisa" uniqKey="Tasanen K" first="Kaisa" last="Tasanen">Kaisa Tasanen</name><affiliation><nlm:aff id="aff3">PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff20">Department of Dermatology and Oulu Center for Cell-Matrix Research, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Anttila, Eija" sort="Anttila, Eija" uniqKey="Anttila E" first="Eija" last="Anttila">Eija Anttila</name><affiliation><nlm:aff id="aff3">PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Children and Adolescents, Oulu University Hospital, PO Box 23, 90029 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Marques, Tiago Reis" sort="Marques, Tiago Reis" uniqKey="Marques T" first="Tiago Reis" last="Marques">Tiago Reis Marques</name><affiliation><nlm:aff id="aff21">Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London SE5 8AF, UK</nlm:aff></affiliation></author><author><name sortKey="Howes, Oliver" sort="Howes, Oliver" uniqKey="Howes O" first="Oliver" last="Howes">Oliver Howes</name><affiliation><nlm:aff id="aff21">Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London SE5 8AF, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff22">MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK</nlm:aff></affiliation></author><author><name sortKey="Politis, Marius" sort="Politis, Marius" uniqKey="Politis M" first="Marius" last="Politis">Marius Politis</name><affiliation><nlm:aff id="aff23">Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London SE5 8AF, UK</nlm:aff></affiliation></author><author><name sortKey="Fahiminiya, Somayyeh" sort="Fahiminiya, Somayyeh" uniqKey="Fahiminiya S" first="Somayyeh" last="Fahiminiya">Somayyeh Fahiminiya</name><affiliation><nlm:aff id="aff5">Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff24">McGill University and Génome Québec Innovation Centre, Montreal, Quebec, QC H3A 0G1, Canada</nlm:aff></affiliation></author><author><name sortKey="Nguyen, Khanh Q" sort="Nguyen, Khanh Q" uniqKey="Nguyen K" first="Khanh Q." last="Nguyen">Khanh Q. Nguyen</name><affiliation><nlm:aff id="aff6">Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada</nlm:aff></affiliation></author><author><name sortKey="Majewski, Jacek" sort="Majewski, Jacek" uniqKey="Majewski J" first="Jacek" last="Majewski">Jacek Majewski</name><affiliation><nlm:aff id="aff5">Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff24">McGill University and Génome Québec Innovation Centre, Montreal, Quebec, QC H3A 0G1, Canada</nlm:aff></affiliation></author><author><name sortKey="Uusimaa, Johanna" sort="Uusimaa, Johanna" uniqKey="Uusimaa J" first="Johanna" last="Uusimaa">Johanna Uusimaa</name><affiliation><nlm:aff id="aff3">PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Children and Adolescents, Oulu University Hospital, PO Box 23, 90029 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Biocenter Oulu, University of Oulu, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Sheridan, Eamonn" sort="Sheridan, Eamonn" uniqKey="Sheridan E" first="Eamonn" last="Sheridan">Eamonn Sheridan</name><affiliation><nlm:aff id="aff1">School of Medicine, University of Leeds, Leeds LS9 7TF, UK</nlm:aff></affiliation></author><author><name sortKey="Brandon, Nicholas J" sort="Brandon, Nicholas J" uniqKey="Brandon N" first="Nicholas J." last="Brandon">Nicholas J. Brandon</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27058446</idno><idno type="pmc">4833436</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833436</idno><idno type="RBID">PMC:4833436</idno><idno type="doi">10.1016/j.ajhg.2016.03.015</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000514</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000514</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Biallelic Mutations in <italic>PDE10A</italic> Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy</title><author><name sortKey="Diggle, Christine P" sort="Diggle, Christine P" uniqKey="Diggle C" first="Christine P." last="Diggle">Christine P. Diggle</name><affiliation><nlm:aff id="aff1">School of Medicine, University of Leeds, Leeds LS9 7TF, UK</nlm:aff></affiliation></author><author><name sortKey="Sukoff Rizzo, Stacey J" sort="Sukoff Rizzo, Stacey J" uniqKey="Sukoff Rizzo S" first="Stacey J." last="Sukoff Rizzo">Stacey J. Sukoff Rizzo</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="Popiolek, Michael" sort="Popiolek, Michael" uniqKey="Popiolek M" first="Michael" last="Popiolek">Michael Popiolek</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="Hinttala, Reetta" sort="Hinttala, Reetta" uniqKey="Hinttala R" first="Reetta" last="Hinttala">Reetta Hinttala</name><affiliation><nlm:aff id="aff3">PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Children and Adolescents, Oulu University Hospital, PO Box 23, 90029 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Biocenter Oulu, University of Oulu, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Schulke, Jan Philip" sort="Schulke, Jan Philip" uniqKey="Schulke J" first="Jan-Philip" last="Schülke">Jan-Philip Schülke</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="Kurian, Manju A" sort="Kurian, Manju A" uniqKey="Kurian M" first="Manju A." last="Kurian">Manju A. Kurian</name><affiliation><nlm:aff id="aff8">Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff9">Department of Neurology, Great Ormond Street Hospital, London WC1N 1EH, UK</nlm:aff></affiliation></author><author><name sortKey="Carr, Ian M" sort="Carr, Ian M" uniqKey="Carr I" first="Ian M." last="Carr">Ian M. Carr</name><affiliation><nlm:aff id="aff1">School of Medicine, University of Leeds, Leeds LS9 7TF, UK</nlm:aff></affiliation></author><author><name sortKey="Markham, Alexander F" sort="Markham, Alexander F" uniqKey="Markham A" first="Alexander F." last="Markham">Alexander F. Markham</name><affiliation><nlm:aff id="aff1">School of Medicine, University of Leeds, Leeds LS9 7TF, UK</nlm:aff></affiliation></author><author><name sortKey="Bonthron, David T" sort="Bonthron, David T" uniqKey="Bonthron D" first="David T." last="Bonthron">David T. Bonthron</name><affiliation><nlm:aff id="aff1">School of Medicine, University of Leeds, Leeds LS9 7TF, UK</nlm:aff></affiliation></author><author><name sortKey="Watson, Christopher" sort="Watson, Christopher" uniqKey="Watson C" first="Christopher" last="Watson">Christopher Watson</name><affiliation><nlm:aff id="aff1">School of Medicine, University of Leeds, Leeds LS9 7TF, UK</nlm:aff></affiliation></author><author><name sortKey="Sharif, Saghira Malik" sort="Sharif, Saghira Malik" uniqKey="Sharif S" first="Saghira Malik" last="Sharif">Saghira Malik Sharif</name><affiliation><nlm:aff id="aff1">School of Medicine, University of Leeds, Leeds LS9 7TF, UK</nlm:aff></affiliation></author><author><name sortKey="Reinhart, Veronica" sort="Reinhart, Veronica" uniqKey="Reinhart V" first="Veronica" last="Reinhart">Veronica Reinhart</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="James, Larry C" sort="James, Larry C" uniqKey="James L" first="Larry C." last="James">Larry C. James</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="Vanase Frawley, Michelle A" sort="Vanase Frawley, Michelle A" uniqKey="Vanase Frawley M" first="Michelle A." last="Vanase-Frawley">Michelle A. Vanase-Frawley</name><affiliation><nlm:aff id="aff10">Pfizer Research and Development, Groton, CT 06340, USA</nlm:aff></affiliation></author><author><name sortKey="Charych, Erik" sort="Charych, Erik" uniqKey="Charych E" first="Erik" last="Charych">Erik Charych</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="Allen, Melanie" sort="Allen, Melanie" uniqKey="Allen M" first="Melanie" last="Allen">Melanie Allen</name><affiliation><nlm:aff id="aff10">Pfizer Research and Development, Groton, CT 06340, USA</nlm:aff></affiliation></author><author><name sortKey="Harms, John" sort="Harms, John" uniqKey="Harms J" first="John" last="Harms">John Harms</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="Schmidt, Christopher J" sort="Schmidt, Christopher J" uniqKey="Schmidt C" first="Christopher J." last="Schmidt">Christopher J. Schmidt</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="Ng, Joanne" sort="Ng, Joanne" uniqKey="Ng J" first="Joanne" last="Ng">Joanne Ng</name><affiliation><nlm:aff id="aff8">Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">Institute of Women’s Health, University College London, London WC1N 1EH, UK</nlm:aff></affiliation></author><author><name sortKey="Pysden, Karen" sort="Pysden, Karen" uniqKey="Pysden K" first="Karen" last="Pysden">Karen Pysden</name><affiliation><nlm:aff id="aff12">Department of Pediatric Neurology, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK</nlm:aff></affiliation></author><author><name sortKey="Strick, Christine" sort="Strick, Christine" uniqKey="Strick C" first="Christine" last="Strick">Christine Strick</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author><author><name sortKey="Vieira, P Ivi" sort="Vieira, P Ivi" uniqKey="Vieira P" first="P Ivi" last="Vieira">P Ivi Vieira</name><affiliation><nlm:aff id="aff3">PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Children and Adolescents, Oulu University Hospital, PO Box 23, 90029 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Mankinen, Katariina" sort="Mankinen, Katariina" uniqKey="Mankinen K" first="Katariina" last="Mankinen">Katariina Mankinen</name><affiliation><nlm:aff id="aff13">Länsi-Pohja Central Hospital, 94100 Kemi, Finland</nlm:aff></affiliation></author><author><name sortKey="Kokkonen, Hannaleena" sort="Kokkonen, Hannaleena" uniqKey="Kokkonen H" first="Hannaleena" last="Kokkonen">Hannaleena Kokkonen</name><affiliation><nlm:aff id="aff14">Department of Clinical Chemistry, University of Oulu, PO Box 5000, 90014, Oulu Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff15">Northern Finland Laboratory Centre, Oulu University Hospital, PO Box 500, 90029 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Kallioinen, Matti" sort="Kallioinen, Matti" uniqKey="Kallioinen M" first="Matti" last="Kallioinen">Matti Kallioinen</name><affiliation><nlm:aff id="aff16">Department of Pathology, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Sormunen, Raija" sort="Sormunen, Raija" uniqKey="Sormunen R" first="Raija" last="Sormunen">Raija Sormunen</name><affiliation><nlm:aff id="aff7">Biocenter Oulu, University of Oulu, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff16">Department of Pathology, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Rinne, Juha O" sort="Rinne, Juha O" uniqKey="Rinne J" first="Juha O." last="Rinne">Juha O. Rinne</name><affiliation><nlm:aff id="aff17">Division of Clinical Neurosciences, Turku University Hospital and University of Turku, PO Box 52, 20521 Turku, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff18">Turku PET Centre, Turku University Hospital and University of Turku, PO Box 52, 20521 Turku, Finland</nlm:aff></affiliation></author><author><name sortKey="Johansson, Jarkko" sort="Johansson, Jarkko" uniqKey="Johansson J" first="Jarkko" last="Johansson">Jarkko Johansson</name><affiliation><nlm:aff id="aff18">Turku PET Centre, Turku University Hospital and University of Turku, PO Box 52, 20521 Turku, Finland</nlm:aff></affiliation></author><author><name sortKey="Alakurtti, Kati" sort="Alakurtti, Kati" uniqKey="Alakurtti K" first="Kati" last="Alakurtti">Kati Alakurtti</name><affiliation><nlm:aff id="aff18">Turku PET Centre, Turku University Hospital and University of Turku, PO Box 52, 20521 Turku, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff19">Department of Diagnostic Radiology, University of Turku and Turku University Hospital, PO Box 52, 20521 Turku, Finland</nlm:aff></affiliation></author><author><name sortKey="Huilaja, Laura" sort="Huilaja, Laura" uniqKey="Huilaja L" first="Laura" last="Huilaja">Laura Huilaja</name><affiliation><nlm:aff id="aff3">PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff20">Department of Dermatology and Oulu Center for Cell-Matrix Research, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Hurskainen, Tiina" sort="Hurskainen, Tiina" uniqKey="Hurskainen T" first="Tiina" last="Hurskainen">Tiina Hurskainen</name><affiliation><nlm:aff id="aff3">PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff20">Department of Dermatology and Oulu Center for Cell-Matrix Research, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Tasanen, Kaisa" sort="Tasanen, Kaisa" uniqKey="Tasanen K" first="Kaisa" last="Tasanen">Kaisa Tasanen</name><affiliation><nlm:aff id="aff3">PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff20">Department of Dermatology and Oulu Center for Cell-Matrix Research, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Anttila, Eija" sort="Anttila, Eija" uniqKey="Anttila E" first="Eija" last="Anttila">Eija Anttila</name><affiliation><nlm:aff id="aff3">PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Children and Adolescents, Oulu University Hospital, PO Box 23, 90029 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Marques, Tiago Reis" sort="Marques, Tiago Reis" uniqKey="Marques T" first="Tiago Reis" last="Marques">Tiago Reis Marques</name><affiliation><nlm:aff id="aff21">Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London SE5 8AF, UK</nlm:aff></affiliation></author><author><name sortKey="Howes, Oliver" sort="Howes, Oliver" uniqKey="Howes O" first="Oliver" last="Howes">Oliver Howes</name><affiliation><nlm:aff id="aff21">Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London SE5 8AF, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff22">MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK</nlm:aff></affiliation></author><author><name sortKey="Politis, Marius" sort="Politis, Marius" uniqKey="Politis M" first="Marius" last="Politis">Marius Politis</name><affiliation><nlm:aff id="aff23">Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London SE5 8AF, UK</nlm:aff></affiliation></author><author><name sortKey="Fahiminiya, Somayyeh" sort="Fahiminiya, Somayyeh" uniqKey="Fahiminiya S" first="Somayyeh" last="Fahiminiya">Somayyeh Fahiminiya</name><affiliation><nlm:aff id="aff5">Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff24">McGill University and Génome Québec Innovation Centre, Montreal, Quebec, QC H3A 0G1, Canada</nlm:aff></affiliation></author><author><name sortKey="Nguyen, Khanh Q" sort="Nguyen, Khanh Q" uniqKey="Nguyen K" first="Khanh Q." last="Nguyen">Khanh Q. Nguyen</name><affiliation><nlm:aff id="aff6">Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada</nlm:aff></affiliation></author><author><name sortKey="Majewski, Jacek" sort="Majewski, Jacek" uniqKey="Majewski J" first="Jacek" last="Majewski">Jacek Majewski</name><affiliation><nlm:aff id="aff5">Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff24">McGill University and Génome Québec Innovation Centre, Montreal, Quebec, QC H3A 0G1, Canada</nlm:aff></affiliation></author><author><name sortKey="Uusimaa, Johanna" sort="Uusimaa, Johanna" uniqKey="Uusimaa J" first="Johanna" last="Uusimaa">Johanna Uusimaa</name><affiliation><nlm:aff id="aff3">PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Children and Adolescents, Oulu University Hospital, PO Box 23, 90029 Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Biocenter Oulu, University of Oulu, PO Box 5000, 90014 Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Sheridan, Eamonn" sort="Sheridan, Eamonn" uniqKey="Sheridan E" first="Eamonn" last="Sheridan">Eamonn Sheridan</name><affiliation><nlm:aff id="aff1">School of Medicine, University of Leeds, Leeds LS9 7TF, UK</nlm:aff></affiliation></author><author><name sortKey="Brandon, Nicholas J" sort="Brandon, Nicholas J" uniqKey="Brandon N" first="Nicholas J." last="Brandon">Nicholas J. Brandon</name><affiliation><nlm:aff id="aff2">Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</nlm:aff></affiliation></author></analytic><series><title level="j">American Journal of Human Genetics</title><idno type="ISSN">0002-9297</idno><idno type="eISSN">1537-6605</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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 <italic>PDE10A</italic> 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.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Hum Genet</journal-id><journal-id journal-id-type="iso-abbrev">Am. J. Hum. Genet</journal-id><journal-title-group><journal-title>American Journal of Human Genetics</journal-title></journal-title-group><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27058446</article-id><article-id pub-id-type="pmc">4833436</article-id><article-id pub-id-type="publisher-id">S0002-9297(16)30050-7</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2016.03.015</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Biallelic Mutations in <italic>PDE10A</italic> Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Diggle</surname><given-names>Christine P.</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn1" ref-type="fn">25</xref></contrib><contrib contrib-type="author"><name><surname>Sukoff Rizzo</surname><given-names>Stacey J.</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="fn1" ref-type="fn">25</xref></contrib><contrib contrib-type="author"><name><surname>Popiolek</surname><given-names>Michael</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="fn1" ref-type="fn">25</xref></contrib><contrib contrib-type="author"><name><surname>Hinttala</surname><given-names>Reetta</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff4" ref-type="aff">4</xref><xref rid="aff5" ref-type="aff">5</xref><xref rid="aff6" ref-type="aff">6</xref><xref rid="aff7" ref-type="aff">7</xref><xref rid="fn1" ref-type="fn">25</xref></contrib><contrib contrib-type="author"><name><surname>Schülke</surname><given-names>Jan-Philip</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="fn1" ref-type="fn">25</xref><xref rid="fn3" ref-type="fn">27</xref></contrib><contrib contrib-type="author"><name><surname>Kurian</surname><given-names>Manju A.</given-names></name><xref rid="aff8" ref-type="aff">8</xref><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Carr</surname><given-names>Ian M.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Markham</surname><given-names>Alexander F.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Bonthron</surname><given-names>David T.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Watson</surname><given-names>Christopher</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Sharif</surname><given-names>Saghira Malik</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Reinhart</surname><given-names>Veronica</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>James</surname><given-names>Larry C.</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Vanase-Frawley</surname><given-names>Michelle A.</given-names></name><xref rid="aff10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>Charych</surname><given-names>Erik</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Allen</surname><given-names>Melanie</given-names></name><xref rid="aff10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>Harms</surname><given-names>John</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Schmidt</surname><given-names>Christopher J.</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Ng</surname><given-names>Joanne</given-names></name><xref rid="aff8" ref-type="aff">8</xref><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><name><surname>Pysden</surname><given-names>Karen</given-names></name><xref rid="aff12" ref-type="aff">12</xref></contrib><contrib contrib-type="author"><name><surname>Strick</surname><given-names>Christine</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Vieira</surname><given-names>Päivi</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Mankinen</surname><given-names>Katariina</given-names></name><xref rid="aff13" ref-type="aff">13</xref></contrib><contrib contrib-type="author"><name><surname>Kokkonen</surname><given-names>Hannaleena</given-names></name><xref rid="aff14" ref-type="aff">14</xref><xref rid="aff15" ref-type="aff">15</xref></contrib><contrib contrib-type="author"><name><surname>Kallioinen</surname><given-names>Matti</given-names></name><xref rid="aff16" ref-type="aff">16</xref></contrib><contrib contrib-type="author"><name><surname>Sormunen</surname><given-names>Raija</given-names></name><xref rid="aff7" ref-type="aff">7</xref><xref rid="aff16" ref-type="aff">16</xref></contrib><contrib contrib-type="author"><name><surname>Rinne</surname><given-names>Juha O.</given-names></name><xref rid="aff17" ref-type="aff">17</xref><xref rid="aff18" ref-type="aff">18</xref></contrib><contrib contrib-type="author"><name><surname>Johansson</surname><given-names>Jarkko</given-names></name><xref rid="aff18" ref-type="aff">18</xref></contrib><contrib contrib-type="author"><name><surname>Alakurtti</surname><given-names>Kati</given-names></name><xref rid="aff18" ref-type="aff">18</xref><xref rid="aff19" ref-type="aff">19</xref></contrib><contrib contrib-type="author"><name><surname>Huilaja</surname><given-names>Laura</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff20" ref-type="aff">20</xref></contrib><contrib contrib-type="author"><name><surname>Hurskainen</surname><given-names>Tiina</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff20" ref-type="aff">20</xref></contrib><contrib contrib-type="author"><name><surname>Tasanen</surname><given-names>Kaisa</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff20" ref-type="aff">20</xref></contrib><contrib contrib-type="author"><name><surname>Anttila</surname><given-names>Eija</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Marques</surname><given-names>Tiago Reis</given-names></name><xref rid="aff21" ref-type="aff">21</xref></contrib><contrib contrib-type="author"><name><surname>Howes</surname><given-names>Oliver</given-names></name><xref rid="aff21" ref-type="aff">21</xref><xref rid="aff22" ref-type="aff">22</xref></contrib><contrib contrib-type="author"><name><surname>Politis</surname><given-names>Marius</given-names></name><xref rid="aff23" ref-type="aff">23</xref></contrib><contrib contrib-type="author"><name><surname>Fahiminiya</surname><given-names>Somayyeh</given-names></name><xref rid="aff5" ref-type="aff">5</xref><xref rid="aff24" ref-type="aff">24</xref></contrib><contrib contrib-type="author"><name><surname>Nguyen</surname><given-names>Khanh Q.</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Majewski</surname><given-names>Jacek</given-names></name><xref rid="aff5" ref-type="aff">5</xref><xref rid="aff24" ref-type="aff">24</xref></contrib><contrib contrib-type="author"><name><surname>Uusimaa</surname><given-names>Johanna</given-names></name><email>johanna.uusimaa@oulu.fi</email><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff4" ref-type="aff">4</xref><xref rid="aff7" ref-type="aff">7</xref><xref rid="fn2" ref-type="fn">26</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib><contrib contrib-type="author"><name><surname>Sheridan</surname><given-names>Eamonn</given-names></name><email>e.sheridan@leeds.ac.uk</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn2" ref-type="fn">26</xref><xref rid="cor2" ref-type="corresp">∗∗</xref></contrib><contrib contrib-type="author"><name><surname>Brandon</surname><given-names>Nicholas J.</given-names></name><email>nick.brandon@azneuro.com</email><xref rid="aff2" ref-type="aff">2</xref><xref rid="fn2" ref-type="fn">26</xref><xref rid="fn3" ref-type="fn">27</xref><xref rid="cor3" ref-type="corresp">∗∗∗</xref></contrib></contrib-group><aff id="aff1"><label>1</label>School of Medicine, University of Leeds, Leeds LS9 7TF, UK</aff><aff id="aff2"><label>2</label>Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA</aff><aff id="aff3"><label>3</label>PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014 Oulu, Finland</aff><aff id="aff4"><label>4</label>Department of Children and Adolescents, Oulu University Hospital, PO Box 23, 90029 Oulu, Finland</aff><aff id="aff5"><label>5</label>Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada</aff><aff id="aff6"><label>6</label>Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada</aff><aff id="aff7"><label>7</label>Biocenter Oulu, University of Oulu, PO Box 5000, 90014 Oulu, Finland</aff><aff id="aff8"><label>8</label>Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK</aff><aff id="aff9"><label>9</label>Department of Neurology, Great Ormond Street Hospital, London WC1N 1EH, UK</aff><aff id="aff10"><label>10</label>Pfizer Research and Development, Groton, CT 06340, USA</aff><aff id="aff11"><label>11</label>Institute of Women’s Health, University College London, London WC1N 1EH, UK</aff><aff id="aff12"><label>12</label>Department of Pediatric Neurology, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK</aff><aff id="aff13"><label>13</label>Länsi-Pohja Central Hospital, 94100 Kemi, Finland</aff><aff id="aff14"><label>14</label>Department of Clinical Chemistry, University of Oulu, PO Box 5000, 90014, Oulu Finland</aff><aff id="aff15"><label>15</label>Northern Finland Laboratory Centre, Oulu University Hospital, PO Box 500, 90029 Oulu, Finland</aff><aff id="aff16"><label>16</label>Department of Pathology, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland</aff><aff id="aff17"><label>17</label>Division of Clinical Neurosciences, Turku University Hospital and University of Turku, PO Box 52, 20521 Turku, Finland</aff><aff id="aff18"><label>18</label>Turku PET Centre, Turku University Hospital and University of Turku, PO Box 52, 20521 Turku, Finland</aff><aff id="aff19"><label>19</label>Department of Diagnostic Radiology, University of Turku and Turku University Hospital, PO Box 52, 20521 Turku, Finland</aff><aff id="aff20"><label>20</label>Department of Dermatology and Oulu Center for Cell-Matrix Research, Oulu University Hospital and University of Oulu, PO Box 5000, 90014 Oulu, Finland</aff><aff id="aff21"><label>21</label>Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London SE5 8AF, UK</aff><aff id="aff22"><label>22</label>MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK</aff><aff id="aff23"><label>23</label>Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London SE5 8AF, UK</aff><aff id="aff24"><label>24</label>McGill University and Génome Québec Innovation Centre, Montreal, Quebec, QC H3A 0G1, Canada</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>johanna.uusimaa@oulu.fi</email></corresp><corresp id="cor2"><label>∗∗</label>Corresponding author <email>e.sheridan@leeds.ac.uk</email></corresp><corresp id="cor3"><label>∗∗∗</label>Corresponding author <email>nick.brandon@azneuro.com</email></corresp><fn id="fn1"><label>25</label><p id="ntpara0010">These authors contributed equally to this manuscript</p></fn><fn id="fn2"><label>26</label><p id="ntpara0015">These authors contributed equally to this manuscript</p></fn><fn id="fn3"><label>27</label><p id="ntpara0020">Present address: Innovative Medicines and Early Development Biotech Unit, AstraZeneca Neuroscience, 141 Portland Street, Cambridge, MA 02139, USA</p></fn></author-notes><pub-date pub-type="ppub"><day>07</day><month>4</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>07</day><month>4</month><year>2016</year></pub-date><volume>98</volume><issue>4</issue><fpage>735</fpage><lpage>743</lpage><history><date date-type="received"><day>28</day><month>1</month><year>2016</year></date><date date-type="accepted"><day>14</day><month>3</month><year>2016</year></date></history><permissions><copyright-statement>© 2016 by The American Society of Human Genetics. All rights reserved.</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder></permissions><related-article related-article-type="article-reference" id="d32e12" ext-link-type="doi" xlink:href="10.1016/j.ajhg.2016.02.015"></related-article><abstract><p>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 <italic>PDE10A</italic> 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.</p></abstract></article-meta><notes><p id="misc0010">Published: April 7, 2016</p></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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