Allelic heterogeneity and abnormal vesicle recycling in PLAA-related neurodevelopmental disorders
Michele Iacomino1, Nadia Houerbi2, Sara Fortuna3
1Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Insights
New genetic variants in the Phospholipase-A2-Activating-Protein (PLAA) gene are linked to neurodevelopmental disorders in children. These PLAA gene defects disrupt vesicle recycling, impacting brain development.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- The human PLAA gene encodes Phospholipase-A2-Activating-Protein (PLAA), crucial for membrane protein trafficking.
- PLAA's PUL domain interacts with p97/VCP, regulating synaptic vesicle recycling.
- While biallelic PLAA variants cause neurodegeneration, the effects of monoallelic variants remain unclear.
Purpose of the Study:
- To investigate the role of monoallelic PLAA variants in neurodevelopmental disorders (NDDs).
- To elucidate the molecular mechanisms underlying PLAA-associated NDDs.
Main Methods:
- Exome and genome sequencing to identify de novo PLAA missense variants.
- Computational analysis and in vitro studies to assess variant effects on protein structure and function.
Main Results:
- Identified de novo missense PLAA variants in children with NDDs (psychomotor regression, ID, ASDs).
- Variants affected conserved residues in the PLAA PUL domain.
- Observed abnormal C-terminal chain arrangements and reduced PLAA-p97/VCP interaction in vitro.
Conclusions:
- Monoallelic PLAA variants contribute to NDDs, expanding allelic and phenotypic heterogeneity.
- Perturbed vesicle recycling due to PLAA genetic defects is a potential mechanism in NDDs.
Abstract:
The human PLAA gene encodes Phospholipase-A2-Activating-Protein (PLAA) involved in trafficking of membrane proteins. Through its PUL domain (PLAP, Ufd3p, and Lub1p), PLAA interacts with p97/VCP modulating synaptic vesicles recycling. Although few families carrying biallelic PLAA variants were reported with progressive neurodegeneration, consequences of monoallelic PLAA variants have not been elucidated. Using exome or genome sequencing we identified PLAA de-novo missense variants, affecting conserved residues within the PUL domain, in children affected with neurodevelopmental disorders (NDDs), including psychomotor regression, intellectual disability (ID) and autism spectrum disorders (ASDs). Computational and in-vitro studies of the identified variants revealed abnormal chain arrangements at C-terminal and reduced PLAA-p97/VCP interaction, respectively. These findings expand both allelic and phenotypic heterogeneity associated to PLAA-related neurological disorders, highlighting perturbed vesicle recycling as a potential disease mechanism in NDDs due to genetic defects of PLAA.
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