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

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 G.L. Mullins, Amanda Bretman, Ruslan Al-Ali, Christian Beetz, Lihadh Al-Gazali, Aisha Al Shamsi, Jason P. LerchJack R. Mellor, Abeer Al Sayegh, Manir Ali, Chris F. Inglehearn, Steven J. Clapcote*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)323-334
Number of pages12
JournalBiological Psychiatry
Issue number4
Publication statusPublished - Aug 1 2022


  • Brain structure
  • Endoplasmic reticulum
  • Intellectual disability
  • Long-term memory
  • PDZD8
  • Synaptic plasticity
  • Mutation/genetics
  • Drosophila
  • Humans
  • Adaptor Proteins, Signal Transducing/genetics
  • Intellectual Disability/genetics
  • Animals
  • Cognitive Dysfunction/genetics
  • Consanguinity
  • Mice
  • Drosophila melanogaster

ASJC Scopus subject areas

  • Biological Psychiatry


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