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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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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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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.
Keywords: Brain structure; Endoplasmic reticulum; Intellectual disability; Long-term memory; PDZD8; Synaptic plasticity
College: Faculty of Medicine, Health and Life Sciences
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).
Issue: 4
Start Page: 323
End Page: 334