Al-Amri, AH, Armstrong, P orcid.org/0000-0001-8735-3762, Amici, M et al. (22 more authors) (2022) PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice and Fruit Flies. Biological Psychiatry, 92 (4). pp. 323-334. ISSN 0006-3223
Abstract
BACKGROUND
The discovery of coding variants in genes that confer risk of intellectual disability (ID) is an important step towards understanding the pathophysiology of this common developmental disability.
METHODS
Homozygosity mapping, whole-exome sequencing and co-segregation analyses were employed 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 and mice with targeted interference of the orthologous gene were utilized. Behavioural, electrophysiological and structural magnetic resonance imaging analyses were conducted for phenotypic testing.
RESULTS
Homozygous premature termination codons in PDZD8, encoding an endoplasmic reticulum-anchored lipid transfer protein, showed co-segregation with syndromic ID in both families. Drosophila 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.
CONCLUSIONS
These 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Ⓒ 2022 Society of Biological Psychiatry. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
Keywords: | Brain structure, Endoplasmic reticulum, Intellectual disability, Long-term memory, PDZD8, Synaptic plasticity |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biology (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Funding Information: | Funder Grant number MRC (Medical Research Council) MR/R014736/1 BBSRC (Biotechnology & Biological Sciences Research Council) BB/R019401/1 NC3Rs Not Known |
Depositing User: | Symplectic Publications |
Date Deposited: | 14 Jan 2022 10:15 |
Last Modified: | 24 Jun 2023 06:41 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.biopsych.2021.12.017 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:182501 |