PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies.
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Authors
Al-Amri, Ahmed H
Armstrong, Paul
Amici, Mascia
Ligneul, Clemence
Rouse, James
El-Asrag, Mohammed E
Pantiru, Andreea
Vancollie, Valerie E
Ng, Hannah WY
Ogbeta, Jennifer A
Goodchild, Kirstie
Ellegood, Jacob
Lelliott, Christopher J
Mullins, Jonathan GL
Bretman, Amanda
Al-Ali, Ruslan
Beetz, Christian
Al-Gazali, Lihadh
Al Shamsi, Aisha
Lerch, Jason P
Mellor, Jack R
Al Sayegh, Abeer
Ali, Manir
Inglehearn, Chris F
Clapcote, Steven J
Publication Date
2022-08-15Journal Title
Biol Psychiatry
ISSN
0006-3223
Publisher
Elsevier BV
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Al-Amri, A. H., Armstrong, P., Amici, M., Ligneul, C., Rouse, J., El-Asrag, M. E., Pantiru, A., et al. (2022). PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies.. Biol Psychiatry https://doi.org/10.1016/j.biopsych.2021.12.017
Abstract
BACKGROUND: The 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. METHODS: Homozygosity 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. RESULTS: Homozygous 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. 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.
Identifiers
External DOI: https://doi.org/10.1016/j.biopsych.2021.12.017
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332897
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
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