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PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies

Ahmed H. Al-Amri Orcid Logo, Paul Armstrong Orcid Logo, Mascia Amici, Clemence Ligneul, James Rouse, Mohammed E. El-Asrag Orcid Logo, Andreea Pantiru, Valerie E. Vancollie Orcid Logo, Hannah W.Y. Ng, Jennifer A. Ogbeta, Kirstie Goodchild, Jacob Ellegood, Christopher J. Lelliott Orcid Logo, Jonathan Mullins Orcid Logo, Amanda Bretman, Ruslan Al-Ali Orcid Logo, Christian Beetz, Lihadh Al-Gazali, Aisha Al Shamsi Orcid Logo, Jason P. Lerch, Jack R. Mellor Orcid Logo, Abeer Al Sayegh Orcid Logo, Manir Ali Orcid Logo, Chris F. Inglehearn Orcid Logo, Steven J. Clapcote Orcid Logo

Biological Psychiatry, Volume: 92, Issue: 4, Pages: 323 - 334

Swansea University Author: Jonathan Mullins Orcid Logo

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DOI (Published version): 10.1016/j.biopsych.2021.12.017

Abstract

BackgroundThe discovery of coding variants in genes that confer risk of intellectual disability (ID) is an important step toward understanding the pathophysiology of this common developmental disability.MethodsHomozygosity mapping, whole-exome sequencing, and cosegregation analyses were used to iden...

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Published in: Biological Psychiatry
ISSN: 0006-3223
Published: Elsevier BV 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa59175
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For in vivo functional studies of the implicated gene&#x2019;s function in cognition, Drosophila melanogaster and mice with targeted interference of the orthologous gene were used. Behavioral, electrophysiological, and structural magnetic resonance imaging analyses were conducted for phenotypic testing.ResultsHomozygous premature termination codons in PDZD8, encoding an endoplasmic reticulum&#x2013;anchored lipid transfer protein, showed cosegregation with syndromic ID in both families. Drosophila melanogaster with knockdown of the PDZD8 ortholog exhibited impaired long-term courtship-based memory. Mice homozygous for a premature termination codon in Pdzd8 exhibited brain structural, hippocampal spatial memory, and synaptic plasticity deficits.ConclusionsThese data demonstrate the involvement of homozygous loss-of-function mutations in PDZD8 in a neurodevelopmental cognitive disorder. Model organisms with manipulation of the orthologous gene replicate aspects of the human phenotype and suggest plausible pathophysiological mechanisms centered on disrupted brain development and synaptic function. These findings are thus consistent with accruing evidence that synaptic defects are a common denominator of ID and other neurodevelopmental conditions.</abstract><type>Journal Article</type><journal>Biological Psychiatry</journal><volume>92</volume><journalNumber>4</journalNumber><paginationStart>323</paginationStart><paginationEnd>334</paginationEnd><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0006-3223</issnPrint><issnElectronic/><keywords>Brain structure; Endoplasmic reticulum; Intellectual disability; Long-term memory; PDZD8; Synaptic plasticity</keywords><publishedDay>15</publishedDay><publishedMonth>8</publishedMonth><publishedYear>2022</publishedYear><publishedDate>2022-08-15</publishedDate><doi>10.1016/j.biopsych.2021.12.017</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>This study was supported by the Medical Research Council (Grant No. MR/R014736/1 [to CFI and SJC]), the Biotechnology and Biological Sciences Research Council (Grant Nos. BB/R019401/1 [to SJC] and BB/R002177/1 [to JRM and MAm]), the Wellcome Trust (Grant No. 101029/Z/1/Z [to JRM and MAm]), the National Centre for the Replacement, Refinement and Reduction of Animals in Research (Grant No. NC/S001719/1 [to AB and SJC]), a Ph.D. scholarship from the Oman Ministry of Higher Education (to AHA-A), a Ph.D. scholarship from the Emma Reid and Leslie Reid Schol-arships and Fellowships Fund (to AP), an M.Sc. studentship from the Ethel and Gwynne Morgan Trust (to HWYN), and a summer internship from the British Association for Psychopharmacology (to KG).</funders><projectreference/><lastEdited>2022-07-26T10:57:57.5335918</lastEdited><Created>2022-01-14T13:24:28.4154859</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Ahmed H.</firstname><surname>Al-Amri</surname><orcid>0000-0001-5846-5618</orcid><order>1</order></author><author><firstname>Paul</firstname><surname>Armstrong</surname><orcid>0000-0001-8735-3762</orcid><order>2</order></author><author><firstname>Mascia</firstname><surname>Amici</surname><order>3</order></author><author><firstname>Clemence</firstname><surname>Ligneul</surname><order>4</order></author><author><firstname>James</firstname><surname>Rouse</surname><order>5</order></author><author><firstname>Mohammed E.</firstname><surname>El-Asrag</surname><orcid>0000-0003-3750-7414</orcid><order>6</order></author><author><firstname>Andreea</firstname><surname>Pantiru</surname><order>7</order></author><author><firstname>Valerie E.</firstname><surname>Vancollie</surname><orcid>0000-0003-1547-1975</orcid><order>8</order></author><author><firstname>Hannah W.Y.</firstname><surname>Ng</surname><order>9</order></author><author><firstname>Jennifer A.</firstname><surname>Ogbeta</surname><order>10</order></author><author><firstname>Kirstie</firstname><surname>Goodchild</surname><order>11</order></author><author><firstname>Jacob</firstname><surname>Ellegood</surname><order>12</order></author><author><firstname>Christopher J.</firstname><surname>Lelliott</surname><orcid>0000-0001-8087-4530</orcid><order>13</order></author><author><firstname>Jonathan</firstname><surname>Mullins</surname><orcid>0000-0003-0144-2962</orcid><order>14</order></author><author><firstname>Amanda</firstname><surname>Bretman</surname><order>15</order></author><author><firstname>Ruslan</firstname><surname>Al-Ali</surname><orcid>0000-0002-0189-3774</orcid><order>16</order></author><author><firstname>Christian</firstname><surname>Beetz</surname><order>17</order></author><author><firstname>Lihadh</firstname><surname>Al-Gazali</surname><order>18</order></author><author><firstname>Aisha Al</firstname><surname>Shamsi</surname><orcid>0000-0001-8757-7782</orcid><order>19</order></author><author><firstname>Jason P.</firstname><surname>Lerch</surname><order>20</order></author><author><firstname>Jack R.</firstname><surname>Mellor</surname><orcid>0000-0002-7706-8105</orcid><order>21</order></author><author><firstname>Abeer Al</firstname><surname>Sayegh</surname><orcid>0000-0002-3097-2420</orcid><order>22</order></author><author><firstname>Manir</firstname><surname>Ali</surname><orcid>0000-0003-3204-3788</orcid><order>23</order></author><author><firstname>Chris F.</firstname><surname>Inglehearn</surname><orcid>0000-0002-5143-2562</orcid><order>24</order></author><author><firstname>Steven J.</firstname><surname>Clapcote</surname><orcid>0000-0002-6662-5690</orcid><order>25</order></author></authors><documents><document><filename>59175__23886__9c4736e50fd24c30adbf62bd8435ff6d.pdf</filename><originalFilename>59175.pdf</originalFilename><uploaded>2022-04-19T15:26:20.6408794</uploaded><type>Output</type><contentLength>2158505</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language><licence>http://creativecommons.org/licenses/by/4.0/</licence></document></documents><OutputDurs/></rfc1807>
spelling 2022-07-26T10:57:57.5335918 v2 59175 2022-01-14 PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies 4cf2dddedbe1dacb506ec925fdbd5b40 0000-0003-0144-2962 Jonathan Mullins Jonathan Mullins true false 2022-01-14 BMS BackgroundThe discovery of coding variants in genes that confer risk of intellectual disability (ID) is an important step toward understanding the pathophysiology of this common developmental disability.MethodsHomozygosity mapping, whole-exome sequencing, and cosegregation analyses were used to identify gene variants responsible for syndromic ID with autistic features in two independent consanguineous families from the Arabian Peninsula. For in vivo functional studies of the implicated gene’s function in cognition, Drosophila melanogaster and mice with targeted interference of the orthologous gene were used. Behavioral, electrophysiological, and structural magnetic resonance imaging analyses were conducted for phenotypic testing.ResultsHomozygous premature termination codons in PDZD8, encoding an endoplasmic reticulum–anchored lipid transfer protein, showed cosegregation with syndromic ID in both families. Drosophila melanogaster with knockdown of the PDZD8 ortholog exhibited impaired long-term courtship-based memory. Mice homozygous for a premature termination codon in Pdzd8 exhibited brain structural, hippocampal spatial memory, and synaptic plasticity deficits.ConclusionsThese data demonstrate the involvement of homozygous loss-of-function mutations in PDZD8 in a neurodevelopmental cognitive disorder. Model organisms with manipulation of the orthologous gene replicate aspects of the human phenotype and suggest plausible pathophysiological mechanisms centered on disrupted brain development and synaptic function. These findings are thus consistent with accruing evidence that synaptic defects are a common denominator of ID and other neurodevelopmental conditions. Journal Article Biological Psychiatry 92 4 323 334 Elsevier BV 0006-3223 Brain structure; Endoplasmic reticulum; Intellectual disability; Long-term memory; PDZD8; Synaptic plasticity 15 8 2022 2022-08-15 10.1016/j.biopsych.2021.12.017 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Another institution paid the OA fee This study was supported by the Medical Research Council (Grant No. MR/R014736/1 [to CFI and SJC]), the Biotechnology and Biological Sciences Research Council (Grant Nos. BB/R019401/1 [to SJC] and BB/R002177/1 [to JRM and MAm]), the Wellcome Trust (Grant No. 101029/Z/1/Z [to JRM and MAm]), the National Centre for the Replacement, Refinement and Reduction of Animals in Research (Grant No. NC/S001719/1 [to AB and SJC]), a Ph.D. scholarship from the Oman Ministry of Higher Education (to AHA-A), a Ph.D. scholarship from the Emma Reid and Leslie Reid Schol-arships and Fellowships Fund (to AP), an M.Sc. studentship from the Ethel and Gwynne Morgan Trust (to HWYN), and a summer internship from the British Association for Psychopharmacology (to KG). 2022-07-26T10:57:57.5335918 2022-01-14T13:24:28.4154859 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Ahmed H. Al-Amri 0000-0001-5846-5618 1 Paul Armstrong 0000-0001-8735-3762 2 Mascia Amici 3 Clemence Ligneul 4 James Rouse 5 Mohammed E. El-Asrag 0000-0003-3750-7414 6 Andreea Pantiru 7 Valerie E. Vancollie 0000-0003-1547-1975 8 Hannah W.Y. Ng 9 Jennifer A. Ogbeta 10 Kirstie Goodchild 11 Jacob Ellegood 12 Christopher J. Lelliott 0000-0001-8087-4530 13 Jonathan Mullins 0000-0003-0144-2962 14 Amanda Bretman 15 Ruslan Al-Ali 0000-0002-0189-3774 16 Christian Beetz 17 Lihadh Al-Gazali 18 Aisha Al Shamsi 0000-0001-8757-7782 19 Jason P. Lerch 20 Jack R. Mellor 0000-0002-7706-8105 21 Abeer Al Sayegh 0000-0002-3097-2420 22 Manir Ali 0000-0003-3204-3788 23 Chris F. Inglehearn 0000-0002-5143-2562 24 Steven J. Clapcote 0000-0002-6662-5690 25 59175__23886__9c4736e50fd24c30adbf62bd8435ff6d.pdf 59175.pdf 2022-04-19T15:26:20.6408794 Output 2158505 application/pdf Version of Record true This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). true eng http://creativecommons.org/licenses/by/4.0/
title PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies
spellingShingle PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies
Jonathan Mullins
title_short PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies
title_full PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies
title_fullStr PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies
title_full_unstemmed PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies
title_sort PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies
author_id_str_mv 4cf2dddedbe1dacb506ec925fdbd5b40
author_id_fullname_str_mv 4cf2dddedbe1dacb506ec925fdbd5b40_***_Jonathan Mullins
author Jonathan Mullins
author2 Ahmed H. Al-Amri
Paul Armstrong
Mascia Amici
Clemence Ligneul
James Rouse
Mohammed E. El-Asrag
Andreea Pantiru
Valerie E. Vancollie
Hannah W.Y. Ng
Jennifer A. Ogbeta
Kirstie Goodchild
Jacob Ellegood
Christopher J. Lelliott
Jonathan Mullins
Amanda Bretman
Ruslan Al-Ali
Christian Beetz
Lihadh Al-Gazali
Aisha Al Shamsi
Jason P. Lerch
Jack R. Mellor
Abeer Al Sayegh
Manir Ali
Chris F. Inglehearn
Steven J. Clapcote
format Journal article
container_title Biological Psychiatry
container_volume 92
container_issue 4
container_start_page 323
publishDate 2022
institution Swansea University
issn 0006-3223
doi_str_mv 10.1016/j.biopsych.2021.12.017
publisher Elsevier BV
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description BackgroundThe discovery of coding variants in genes that confer risk of intellectual disability (ID) is an important step toward understanding the pathophysiology of this common developmental disability.MethodsHomozygosity mapping, whole-exome sequencing, and cosegregation analyses were used to identify gene variants responsible for syndromic ID with autistic features in two independent consanguineous families from the Arabian Peninsula. For in vivo functional studies of the implicated gene’s function in cognition, Drosophila melanogaster and mice with targeted interference of the orthologous gene were used. Behavioral, electrophysiological, and structural magnetic resonance imaging analyses were conducted for phenotypic testing.ResultsHomozygous premature termination codons in PDZD8, encoding an endoplasmic reticulum–anchored lipid transfer protein, showed cosegregation with syndromic ID in both families. Drosophila melanogaster with knockdown of the PDZD8 ortholog exhibited impaired long-term courtship-based memory. Mice homozygous for a premature termination codon in Pdzd8 exhibited brain structural, hippocampal spatial memory, and synaptic plasticity deficits.ConclusionsThese data demonstrate the involvement of homozygous loss-of-function mutations in PDZD8 in a neurodevelopmental cognitive disorder. Model organisms with manipulation of the orthologous gene replicate aspects of the human phenotype and suggest plausible pathophysiological mechanisms centered on disrupted brain development and synaptic function. These findings are thus consistent with accruing evidence that synaptic defects are a common denominator of ID and other neurodevelopmental conditions.
published_date 2022-08-15T04:16:16Z
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