Dataset Information

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

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.

SUBMITTER: Al-Amri AH

PROVIDER: S-EPMC9302898 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Al-Amri Ahmed H AH Armstrong Paul P Amici Mascia M Ligneul Clemence C Rouse James J El-Asrag Mohammed E ME Pantiru Andreea A Vancollie Valerie E VE Ng Hannah W Y HWY Ogbeta Jennifer A JA Goodchild Kirstie K Ellegood Jacob J Lelliott Christopher J CJ Mullins Jonathan G L JGL Bretman Amanda A Al-Ali Ruslan R Beetz Christian C Al-Gazali Lihadh L Al Shamsi Aisha A Lerch Jason P JP Mellor Jack R JR Al Sayegh Abeer A Ali Manir M Inglehearn Chris F CF Clapcote Steven J SJ

Biological psychiatry 20220111 4

<h4>Background</h4>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.<h4>Methods</h4>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 im ...[more]

PMID: 35227461

Similar Datasets

Project description:BackgroundIntellectual developmental disorder with autism and dysmorphic facies (IDDADF) is a rare syndromic intellectual disability (ID) caused by homozygous disruption of PDZD8 (PDZ domain-containing protein 8), an integral endoplasmic reticulum (ER) protein. All four previously identified IDDADF cases exhibit autistic behavior, with autism spectrum disorder (ASD) diagnosed in three cases. To determine whether autistic behavior is a common outcome of PDZD8 disruption, we studied a third family with biallelic mutation of PDZD8 (family C) and further characterized PDZD8-deficient (Pdzd8tm1b) mice that exhibit stereotyped motor behavior relevant to ASD.MethodsHomozygosity mapping, whole-exome sequencing, and cosegregation analysis were used to identify the PDZD8 variant responsible for IDDADF, including diagnoses of ASD, in consanguineous family C. To assess the in vivo effect of PDZD8 disruption on social responses and related phenotypes, behavioral, structural magnetic resonance imaging, and microscopy analyses were conducted on the Pdzd8tm1b mouse line. Metabolic activity was profiled using sealed metabolic cages.ResultsThe discovery of a third family with IDDADF caused by biallelic disruption of PDZD8 permitted identification of a core clinical phenotype consisting of developmental delay, ID, autism, and facial dysmorphism. In addition to impairments in social recognition and social odor discrimination, Pdzd8tm1b mice exhibit increases in locomotor activity (dark phase only) and metabolic rate (both lights-on and dark phases), and decreased plasma triglyceride in males. In the brain, Pdzd8tm1b mice exhibit increased levels of accessory olfactory bulb volume, primary olfactory cortex volume, dendritic spine density, and ER stress- and mitochondrial fusion-related transcripts, as well as decreased levels of cerebellar nuclei volume and adult neurogenesis.LimitationsThe total number of known cases of PDZD8-related IDDADF remains low. Some mouse experiments in the study did not use balanced numbers of males and females. The assessment of ER stress and mitochondrial fusion markers did not extend beyond mRNA levels.ConclusionsOur finding that the Pdzd8tm1b mouse model and all six known cases of IDDADF exhibit autistic behavior, with ASD diagnosed in five cases, identifies this trait as a common outcome of biallelic disruption of PDZD8 in humans and mice. Other abnormalities exhibited by Pdzd8tm1b mice suggest that the range of comorbidities associated with PDZD8 deficiency may be wider than presently recognized.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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