AUTHOR=Iacomino Michele , Houerbi Nadia , Fortuna Sara , Howe Jennifer , Li Shan , Scorrano Giovanna , Riva Antonella , Cheng Kai-Wen , Steiman Mandy , Peltekova Iskra , Yusuf Afiqah , Baldassari Simona , Tamburro Serena , Scudieri Paolo , Musante Ilaria , Di Ludovico Armando , Guerrisi Sara , Balagura Ganna , Corsello Antonio , Efthymiou Stephanie , Murphy David , Uva Paolo , Verrotti Alberto , Fiorillo Chiara , Delvecchio Maurizio , Accogli Andrea , Elsabbagh Mayada , Houlden Henry , Scherer Stephen W. , Striano Pasquale , Zara Federico , Chou Tsui-Fen , Salpietro Vincenzo TITLE=Allelic heterogeneity and abnormal vesicle recycling in PLAA-related neurodevelopmental disorders JOURNAL=Frontiers in Molecular Neuroscience VOLUME=17 YEAR=2024 URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2024.1268013 DOI=10.3389/fnmol.2024.1268013 ISSN=1662-5099 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.