1. Biallelic PI4KA variants cause neurological, intestinal and immunological disease
- Author
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Salter, Claire G, Cai, Yiying, Lo, Bernice, Helman, Guy, Taylor, Henry, McCartney, Amber, Leslie, Joseph S, Accogoli, Andrea, Zara, Frederico, Traverso, Monica, Fasham, James, Lees, Joshua A, Ferla, Matteo, Chioza, Barry A, Wenger, Olivia, Scott, Ethan, Cross, Harold E, Crawford, Joanna, Warshawsky, Ilka, Keisling, Matthew, Agamanolis, Dimitris, Melver, Catherine Ward, Cox, Helen, Elawad, Mamoun, Marton, Tamas, Wakeling, Matthew, Holzinger, Dirk, Tippelt, Stephan, Munteanu, Martin, Valcheva, Deyana, Deal, Christin, Van Meerbeke, Sara, Vockley, Catherine Walsh, Butte, Manish J, Acar, Utkucan, van der Knaap, Marjo S, Korenke, G Christoph, Kotzaeridou, Urania, Balla, Tamas, Simons, Cas, Uhlig, Holm H, Crosby, Andrew H, De Camilli, Pietro, Wolf, Nicole I, and Baple, Emma L
- Subjects
Digestive Diseases ,Pediatric ,1.1 Normal biological development and functioning ,Aetiology ,2.1 Biological and endogenous factors ,Underpinning research ,Oral and gastrointestinal ,Female ,Hereditary Central Nervous System Demyelinating Diseases ,Humans ,Intestinal Atresia ,Male ,Minor Histocompatibility Antigens ,Pedigree ,Phosphotransferases (Alcohol Group Acceptor) ,Polymorphism ,Single Nucleotide ,Primary Immunodeficiency Diseases ,hypomyelinating leukodystrophy ,multiple intestinal atresia ,PI4KA ,FAM126A ,TTC7A ,PI4KA ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα's role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions. Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes probably stem from impairment of PI4KIIIα-TTC7-FAM126's organ-specific functions, due to defective catalytic activity or altered intra-complex functional interactions. Together, these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex.
- Published
- 2021