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PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies
Biological Psychiatry, Volume: 92, Issue: 4, Pages: 323 - 334
Swansea University Author:
Jonathan Mullins
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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...
Published in: | Biological Psychiatry |
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2022
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<?xml version="1.0"?><rfc1807><datestamp>2022-07-26T10:57:57.5335918</datestamp><bib-version>v2</bib-version><id>59175</id><entry>2022-01-14</entry><title>PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies</title><swanseaauthors><author><sid>4cf2dddedbe1dacb506ec925fdbd5b40</sid><ORCID>0000-0003-0144-2962</ORCID><firstname>Jonathan</firstname><surname>Mullins</surname><name>Jonathan Mullins</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2022-01-14</date><deptcode>BMS</deptcode><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 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.</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> |
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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 |
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Biological Psychiatry |
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92 |
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323 |
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2022 |
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Swansea University |
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0006-3223 |
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10.1016/j.biopsych.2021.12.017 |
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Elsevier BV |
college_str |
Faculty of Medicine, Health and Life Sciences |
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facultyofmedicinehealthandlifesciences |
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Faculty of Medicine, Health and Life Sciences |
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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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1763754090846748672 |
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11.019224 |