ArticleJournal of clinical immunology2024
Biallelic PI4KA Mutations Disrupt B-Cell Metabolism and Cause B-Cell Lymphopenia and Hypogammaglobulinemia.
Article in Journal of clinical immunology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- A guide to B cell metabolism.Nature reviews. Immunology · 2026Review
- E-Syt1 recruits PI4KA to endoplasmic reticulum-plasma membrane junctions to enhance PI4P synthesis.Science China. Life sciences · 2026Article
- Multi-omics and artificial intelligence for precision drug discovery and potential clinical applications.Signal transduction and targeted therapy · 2026Review
- Sequential MALDI-MSI-Based Multiomics Reveals Spatial Lipid, Glycan, and Tryptic Peptide Signatures in Breast Tumor Histopathology.Analytical chemistry · 2026Article
- A Gut Feeling: An Exploratory Multi-Omics Study of Gut Microbiome Dysbiosis and Metabolome and Lipidome Alterations in GATA2 Deficiency.International journal of molecular sciences · 2026Article
- Cerebrospinal fluid CEFA composition is enriched in saturated fatty acids and it is altered in Alzheimer's disease.Journal of lipid research · 2026Article
- Spatial dynamics in health and disease: from neurodevelopment to therapeutic target identification for inflammatory diseases.Signal transduction and targeted therapy · 2026Article
- Phosphatidylinositol 4-phosphate; A minor lipid with multiple personalities.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2025Review
- Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee.Journal of human immunity · 2025Article
- FNIP1 Deficiency: Pathophysiology and Clinical Manifestations of a Rare Syndromic Primary Immunodeficiency.Current issues in molecular biology · 2025Review
- Phosphoinositide Metabolism: Biochemistry, Physiology and Genetic Disorders.Journal of inherited metabolic disease · 2025Review
- Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohort.Frontiers in immunology · 2025Observational
- Differential gene expression profiling and machine learning-based discovery of key genetic markers in VTE and CKD.Frontiers in immunology · 2025Article
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Authors and funding
55 authors.
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Abstract
purposePI4KA-related disorder is a highly clinically variable condition characterized by neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus) and gastrointestinal (inflammatory bowel disease and multiple intestinal atresia) manifestations. Although features consistent with immunodeficiency (autoimmunity/autoinflammation and recurrent infections) have been reported in a subset of patients, the burden of B-cell deficiency and hypogammaglobulinemia has not been extensively investigated. We sought to describe the clinical presentation and manifestations of patients with PI4KA-related disorder and to investigate the metabolic consequences of biallelic PI4KA variants in B cells.
methodsClinical data from patients with PI4KA variants were obtained. Multi-omics analyses combining transcriptome, proteome, lipidome and metabolome analyses in conjunction with functional assays were performed in EBV-transformed B cells.
resultsClinical and laboratory data of 13 patients were collected. Recurrent infections (7/13), autoimmune/autoinflammatory manifestations (5/13), B-cell deficiency (8/13) and hypogammaglobulinemia (8/13) were frequently observed. Patients' B cells frequently showed increased transitional and decreased switched memory B-cell subsets. Pathway analyses based on differentially expressed transcripts and proteins confirmed the central role of PI4KA in B cell differentiation with altered B-cell receptor (BCR) complex and signalling. By altering lipids production and tricarboxylic acid cycle regulation, and causing increased endoplasmic reticulum stress, biallelic PI4KA mutations disrupt B cell metabolism inducing mitochondrial dysfunction. As a result, B cells show hyperactive PI3K/mTOR pathway, increased autophagy and deranged cytoskeleton organization.
conclusionBy altering lipid metabolism and TCA cycle, impairing mitochondrial activity, hyperactivating mTOR pathway and increasing autophagy, PI4KA-related disorder causes a syndromic inborn error of immunity presenting with B-cell deficiency and hypogammaglobulinemia.
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