PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic‐dyskinetic encephalopathy
Abstract Objective 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 regul...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-09-01
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| Series: | Annals of Clinical and Translational Neurology |
| Online Access: | https://doi.org/10.1002/acn3.51634 |
| _version_ | 1811210209799962624 |
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| author | Hormos Salimi Dafsari Joshua G. Pemberton Elizabeth A. Ferrer Tony Yammine Chantal Farra Mohammad Hasan Mohammadi Ehsan Ghayoor Karimiani Narges Hashemi Mirna Souaid Sandra Sabbagh Paria Najarzadeh Torbati Suliman Khan Emmanuel Roze Andres Moreno‐De‐Luca Aida M. Bertoli‐Avella Henry Houlden Tamas Balla Reza Maroofian |
| author_facet | Hormos Salimi Dafsari Joshua G. Pemberton Elizabeth A. Ferrer Tony Yammine Chantal Farra Mohammad Hasan Mohammadi Ehsan Ghayoor Karimiani Narges Hashemi Mirna Souaid Sandra Sabbagh Paria Najarzadeh Torbati Suliman Khan Emmanuel Roze Andres Moreno‐De‐Luca Aida M. Bertoli‐Avella Henry Houlden Tamas Balla Reza Maroofian |
| author_sort | Hormos Salimi Dafsari |
| collection | DOAJ |
| description | Abstract Objective 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. Methods 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. Results 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. Interpretation Our study establishes the genotype–phenotype spectrum of PI4K‐associated NDD and highlights several commonalities with other innate errors of intracellular trafficking. |
| first_indexed | 2024-04-12T04:51:48Z |
| format | Article |
| id | doaj.art-e661a9bb4241478abb777acab28ee5c0 |
| institution | Directory Open Access Journal |
| issn | 2328-9503 |
| language | English |
| last_indexed | 2024-04-12T04:51:48Z |
| publishDate | 2022-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Annals of Clinical and Translational Neurology |
| spelling | doaj.art-e661a9bb4241478abb777acab28ee5c02022-12-22T03:47:17ZengWileyAnnals of Clinical and Translational Neurology2328-95032022-09-01991345135810.1002/acn3.51634PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic‐dyskinetic encephalopathyHormos Salimi Dafsari0Joshua G. Pemberton1Elizabeth A. Ferrer2Tony Yammine3Chantal Farra4Mohammad Hasan Mohammadi5Ehsan Ghayoor Karimiani6Narges Hashemi7Mirna Souaid8Sandra Sabbagh9Paria Najarzadeh Torbati10Suliman Khan11Emmanuel Roze12Andres Moreno‐De‐Luca13Aida M. Bertoli‐Avella14Henry Houlden15Tamas Balla16Reza Maroofian17Department of Pediatrics Faculty of Medicine and University Hospital Cologne, University of Cologne Kerpener Str. 62 50937 Köln GermanySection on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver NICHD National Institutes of Health Bethesda Maryland USASection on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver NICHD National Institutes of Health Bethesda Maryland USAMedical Genetics Unit Saint Joseph University Beirut LebanonMedical Genetics Unit Saint Joseph University Beirut LebanonDepartment of Pediatrics Zabol University of Medical Sciences Zabol IranMolecular and Clinical Sciences Institute St. George's, University of London Cranmer Terrace London UKDepartment of Pediatric Neurology, Faculty of Medicine Mashhad University of Medical Sciences Mashhad IranMedical Genetics Unit Saint Joseph University Beirut LebanonDepartment of Genetics Hotel Dieu de France Medical Center Beirut LebanonDepartment of Medical Genetics Next Generation Genetic Polyclinic Mashhad IranCENTOGENE GmbH Rostock GermanyCNRS, INSERM, Institut du Cerveau (ICM) Sorbonne Université Paris 75013 FranceDepartment of Radiology, Diagnostic Medicine Institute Autism & Developmental Medicine Institute, Genomic Medicine Institute, Geisinger Danville Pennsylvania USACENTOGENE GmbH Rostock GermanyDepartment of Neuromuscular Diseases UCL Queen Square Institute of Neurology Queen Square London UKSection on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver NICHD National Institutes of Health Bethesda Maryland USADepartment of Neuromuscular Diseases UCL Queen Square Institute of Neurology Queen Square London UKAbstract Objective 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. Methods 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. Results 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. Interpretation Our study establishes the genotype–phenotype spectrum of PI4K‐associated NDD and highlights several commonalities with other innate errors of intracellular trafficking.https://doi.org/10.1002/acn3.51634 |
| spellingShingle | Hormos Salimi Dafsari Joshua G. Pemberton Elizabeth A. Ferrer Tony Yammine Chantal Farra Mohammad Hasan Mohammadi Ehsan Ghayoor Karimiani Narges Hashemi Mirna Souaid Sandra Sabbagh Paria Najarzadeh Torbati Suliman Khan Emmanuel Roze Andres Moreno‐De‐Luca Aida M. Bertoli‐Avella Henry Houlden Tamas Balla Reza Maroofian PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic‐dyskinetic encephalopathy Annals of Clinical and Translational Neurology |
| title | PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic‐dyskinetic encephalopathy |
| title_full | PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic‐dyskinetic encephalopathy |
| title_fullStr | PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic‐dyskinetic encephalopathy |
| title_full_unstemmed | PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic‐dyskinetic encephalopathy |
| title_short | PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic‐dyskinetic encephalopathy |
| title_sort | pi4k2a deficiency causes innate error in intracellular trafficking with developmental and epileptic dyskinetic encephalopathy |
| url | https://doi.org/10.1002/acn3.51634 |
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