PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic-dyskinetic encephalopathy.
Journal
Annals of clinical and translational neurology
ISSN: 2328-9503
Titre abrégé: Ann Clin Transl Neurol
Pays: United States
ID NLM: 101623278
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
revised:
07
07
2022
received:
10
06
2022
accepted:
08
07
2022
pubmed:
27
7
2022
medline:
14
9
2022
entrez:
26
7
2022
Statut:
ppublish
Résumé
Intracellular signaling networks rely on proper membrane organization to control an array of cellular processes such as metabolism, proliferation, apoptosis, and macroautophagy in eukaryotic cells and organisms. Phosphatidylinositol 4-phosphate (PI4P) emerged as an essential regulatory lipid within organelle membranes that defines their lipid composition and signaling properties. PI4P is generated by four distinct phosphatidylinositol 4-kinases (PI4K) in mammalian cells: PI4KA, PI4KB, PI4K2A, PI4K2B. Animal models and human genetic studies suggest vital roles of PI4K enzymes in development and function of various organs, including the nervous system. Bi-allelic variants in PI4KA were recently associated with neurodevelopmental disorders (NDD), brain malformations, leukodystrophy, primary immunodeficiency, and inflammatory bowel disease. Here, we describe patients from two unrelated consanguineous families with PI4K2A deficiency and functionally explored the pathogenic mechanism. Two patients with PI4K2A deficiency were identified by exome sequencing, presenting with developmental and epileptic-dyskinetic encephalopathy. Neuroimaging showed corpus callosum dysgenesis, diffuse white matter volume loss, and hypoplastic vermis. In addition to NDD, we observed recurrent infections and death at toddler age. We further explored identified variants with cellular assays. This clinical presentation overlaps with what was previously reported in two affected siblings with homozygous nonsense PI4K2A variant. Cellular studies analyzing these human variants confirmed their deleterious effect on PI4K2A activity and, together with the central role of PI4K2A in Rab7-associated vesicular trafficking, establish a link between late endosome-lysosome defects and NDD. Our study establishes the genotype-phenotype spectrum of PI4K-associated NDD and highlights several commonalities with other innate errors of intracellular trafficking.
Identifiants
pubmed: 35880319
doi: 10.1002/acn3.51634
pmc: PMC9463957
doi:
Substances chimiques
Minor Histocompatibility Antigens
0
Phosphotransferases (Alcohol Group Acceptor)
EC 2.7.1.-
phosphatidylinositol phosphate 4-kinase
EC 2.7.1.67
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1345-1358Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NICHD NIH HHS
ID : R01 HD104938
Pays : United States
Organisme : Wellcome Trust
ID : WT104033AIA
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT093205
Pays : United Kingdom
Informations de copyright
© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
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