ArticleAnnals of clinical and translational neurology2022
PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic-dyskinetic encephalopathy.
Article in Annals of clinical and translational neurology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 23 citations in OpenAlex.
- PPP1R21-Related neurodevelopmental disorder: Phenotypic delineation, variant spectrum, and pathophysiological mechanisms.Neurogenetics · 2026Review
- Data-Driven Insights into Hyperkinetic Disorders in Neurodevelopmental Syndromes and Epileptic Encephalopathies.Movement disorders clinical practice · 2026Review
- Canonical pathways and selective mechanisms of autophagy in inflammatory bowel disease.Advanced biotechnology · 2026Review
- Recessive Loss of PI4K2A Function Causes a Developmental and Epileptic Dyskinetic Encephalopathy with Prominent Orolingual Dyskinesia.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- Phosphatidylinositol 4-phosphate; A minor lipid with multiple personalities.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2025Review
- Phosphoinositide Metabolism: Biochemistry, Physiology and Genetic Disorders.Journal of inherited metabolic disease · 2025Review
- Article
- The expanding clinical and genetic spectrum of DYNC1H1-related disorders.Brain : a journal of neurology · 2025Article
- Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis inAutophagy · 2025Article
- An update on autophagy disorders.Journal of inherited metabolic disease · 2025Review
- Expanding the phenotype of PPP1R21-related neurodevelopmental disorder.Clinical genetics · 2024Article
- Biallelic BORCS8 variants cause an infantile-onset neurodegenerative disorder with altered lysosome dynamics.Brain : a journal of neurology · 2024Article
- Phosphoinositide switches in cell physiology - From molecular mechanisms to disease.The Journal of biological chemistry · 2024Review
- Lysosomes in senescence and aging.EMBO reports · 2023Review
- Novel Genetic and Phenotypic Expansion inGenes · 2023Article
- Atopy and Elevation of IgE, IgG3, and IgG4 May Be Risk Factors for Post COVID-19 Condition in Children and Adolescents.Children (Basel, Switzerland) · 2023Article
- A Plethora of Functions Condensed into Tiny Phospholipids: The Story of PI4P and PI(4,5)PCells · 2023Review
- The PITT pathway: Keeping lysosomes young.Clinical and translational medicine · 2022Article
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Authors and funding
18 authors at 11 institutions in 6 countries.
Funding
Abstract
objectiveIntracellular 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.
methodsTwo 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.
resultsThis 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.
interpretationOur study establishes the genotype-phenotype spectrum of PI4K-associated NDD and highlights several commonalities with other innate errors of intracellular trafficking.
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