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与神经发育障碍相关的等位基因异质性和异常囊泡循环

Allelic heterogeneity and abnormal vesicle recycling in -related neurodevelopmental disorders.

作者信息

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

机构信息

Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, United States.

出版信息

Front Mol Neurosci. 2024 Apr 8;17:1268013. doi: 10.3389/fnmol.2024.1268013. eCollection 2024.

DOI:
10.3389/fnmol.2024.1268013
PMID:38650658
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11033462/
Abstract

The human 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 variants were reported with progressive neurodegeneration, consequences of monoallelic variants have not been elucidated. Using exome or genome sequencing we identified 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 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 -related neurological disorders, highlighting perturbed vesicle recycling as a potential disease mechanism in NDDs due to genetic defects of PLAA.

摘要

人类基因编码参与膜蛋白运输的磷脂酶A2激活蛋白（PLAA）。通过其PUL结构域（PLAP、Ufd3p和Lub1p），PLAA与p97/VCP相互作用，调节突触小泡循环。尽管报道了少数携带双等位基因变异的家族患有进行性神经退行性疾病，但单等位基因变异的后果尚未阐明。我们使用外显子组或基因组测序，在患有神经发育障碍（NDD）的儿童中鉴定出影响PUL结构域内保守残基的错义变异，这些儿童包括精神运动发育迟缓、智力残疾（ID）和自闭症谱系障碍（ASD）。对所鉴定变异的计算和研究分别揭示了C末端异常的链排列和PLAA-p97/VCP相互作用的减少。这些发现扩展了与相关神经系统疾病相关的等位基因和表型异质性，突出了由于PLAA的遗传缺陷导致的囊泡循环紊乱作为NDD潜在的疾病机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfc8/11033462/027c5974dd87/fnmol-17-1268013-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfc8/11033462/e232a1700179/fnmol-17-1268013-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfc8/11033462/fd6562e44106/fnmol-17-1268013-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfc8/11033462/07189cfc309d/fnmol-17-1268013-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfc8/11033462/027c5974dd87/fnmol-17-1268013-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfc8/11033462/e232a1700179/fnmol-17-1268013-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfc8/11033462/fd6562e44106/fnmol-17-1268013-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfc8/11033462/07189cfc309d/fnmol-17-1268013-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfc8/11033462/027c5974dd87/fnmol-17-1268013-g0004.jpg

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