Iacomino, Michele;
Houerbi, Nadia;
Fortuna, Sara;
Howe, Jennifer;
Li, Shan;
Scorrano, Giovanna;
Riva, Antonella;
... Salpietro, Vincenzo; + view all
(2024)
Allelic heterogeneity and abnormal vesicle recycling in PLAA-related neurodevelopmental disorders.
Frontiers in Molecular Neuroscience
, 17
, Article 1268013. 10.3389/fnmol.2024.1268013.
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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.
| Type: | Article |
|---|---|
| Title: | Allelic heterogeneity and abnormal vesicle recycling in PLAA-related neurodevelopmental disorders |
| Location: | Switzerland |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fnmol.2024.1268013 |
| Publisher version: | http://dx.doi.org/10.3389/fnmol.2024.1268013 |
| Language: | English |
| Additional information: | © 2024 Iacomino, Houerbi, Fortuna, Howe, Li, Scorrano, Riva, Cheng, Steiman, Peltekova, Yusuf, Baldassari, Tamburro, Scudieri, Musante, Di Ludovico, Guerrisi, Balagura, Corsello, Efthymiou, Murphy, Uva, Verrotti, Fiorillo, Delvecchio, Accogli, Elsabbagh, Houlden, Scherer, Striano, Zara, Chou and Salpietro. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Keywords: | PLAA gene, de novo variants, neurodevelopmental disorders, synaptic transmission, SNAREopathies, developmental regression |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10191939 |
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