Universität zu Köln

Dafsari, Hormos Salimi, Pemberton, Joshua G., Ferrer, Elizabeth A., Yammine, Tony, Farra, Chantal, Mohammadi, Mohammad Hasan, Karimiani, Ehsan Ghayoor, Hashemi, Narges, Souaid, Mirna ORCID: 0000-0001-8950-3170, Sabbagh, Sandra, Torbati, Paria Najarzadeh, Khan, Suliman ORCID: 0000-0002-0745-7834, Roze, Emmanuel, Moreno-De-Luca, Andres, Bertoli-Avella, Aida M., Houlden, Henry, Balla, Tamas and Maroofian, Reza (2022). PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic-dyskinetic encephalopathy. Ann. Clin. Transl. Neurol., 9 (9). S. 1345 - 1359. HOBOKEN: WILEY. ISSN 2328-9503

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dafsari, Hormos Salimi UNSPECIFIED UNSPECIFIED UNSPECIFIED Pemberton, Joshua G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ferrer, Elizabeth A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yammine, Tony UNSPECIFIED UNSPECIFIED UNSPECIFIED Farra, Chantal UNSPECIFIED UNSPECIFIED UNSPECIFIED Mohammadi, Mohammad Hasan UNSPECIFIED UNSPECIFIED UNSPECIFIED Karimiani, Ehsan Ghayoor UNSPECIFIED UNSPECIFIED UNSPECIFIED Hashemi, Narges UNSPECIFIED UNSPECIFIED UNSPECIFIED Souaid, Mirna UNSPECIFIED orcid.org/0000-0001-8950-3170 UNSPECIFIED Sabbagh, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Torbati, Paria Najarzadeh UNSPECIFIED UNSPECIFIED UNSPECIFIED Khan, Suliman UNSPECIFIED orcid.org/0000-0002-0745-7834 UNSPECIFIED Roze, Emmanuel UNSPECIFIED UNSPECIFIED UNSPECIFIED Moreno-De-Luca, Andres UNSPECIFIED UNSPECIFIED UNSPECIFIED Bertoli-Avella, Aida M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Houlden, Henry UNSPECIFIED UNSPECIFIED UNSPECIFIED Balla, Tamas UNSPECIFIED UNSPECIFIED UNSPECIFIED Maroofian, Reza UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-696325
DOI:	10.1002/acn3.51634
Journal or Publication Title:	Ann. Clin. Transl. Neurol.
Volume:	9
Number:	9
Page Range:	S. 1345 - 1359
Date:	2022
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	2328-9503
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PHOSPHATIDYLINOSITOL 4-KINASE; REVEALS; 4-PHOSPHATE Multiple languages Clinical Neurology; Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69632