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.
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 language | English |
|---|---|
| Pages (from-to) | 323-334 |
| Number of pages | 12 |
| Journal | Biological Psychiatry |
| Volume | 92 |
| Issue number | 4 |
| Early online date | 11 Jan 2022 |
| DOIs | |
| Publication status | E-pub ahead of print - 11 Jan 2022 |
Bibliographical note
Funding Information: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 Scholarships 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). We thank both families who participated in this study. We thank Tim Munsey, Ben Slater, Georgia Hale, Katharine Wiltshire, Alix Stonehouse, Frances Moore, Zoe Hewitson, Amy Aspinall, Stephen Pickett, Shivali Kohli, and Tom Wainwright for technical assistance. RA-A and CB are employees of Centogene GmbH. All other authors report no biomedical financial interests or potential conflicts of interest.
Funding Information:
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 Scholarships 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).
Publisher Copyright:
© 2022 Society of Biological Psychiatry
Keywords
- Brain structure
- Endoplasmic reticulum
- Intellectual disability
- Long-term memory
- PDZD8
- Synaptic plasticity