| Literature DB >> 34415310 |
Claire G Salter1,2, Yiying Cai3,4,5,6, Bernice Lo7,8, Guy Helman9,10, Henry Taylor11, Amber McCartney3,4,5,6, Joseph S Leslie1, Andrea Accogli12, Federico Zara12, Monica Traverso12, James Fasham1,13, Joshua A Lees4, Matteo P Ferla14, Barry A Chioza1, Olivia Wenger15, Ethan Scott15, Harold E Cross16, Joanna Crawford10, Ilka Warshawsky17, Matthew Keisling17, Dimitris Agamanolis17, Catherine Ward Melver17, Helen Cox18, Mamoun Elawad19, Tamas Marton20, Matthew N Wakeling1, Dirk Holzinger21, Stephan Tippelt21, Martin Munteanu22, Deyana Valcheva23, Christin Deal24, Sara Van Meerbeke24, Catherine Walsh Vockley25, Manish J Butte26, Utkucan Acar26, Marjo S van der Knaap27,28, G Christoph Korenke29, Urania Kotzaeridou30, Tamas Balla31, Cas Simons9,10, Holm H Uhlig32,33,34, Andrew H Crosby1, Pietro De Camilli3,4,5,6,35, Nicole I Wolf27,28, Emma L Baple1,13.
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.Entities:
Keywords: zzm321990 PI4KAzzm321990 ; FAM126A; TTC7A; hypomyelinating leukodystrophy; multiple intestinal atresia
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Year: 2021 PMID： 34415310 PMCID： PMC8719846 DOI： 10.1093/brain/awab313
Source DB: PubMed Journal: Brain ISSN： 0006-8950 Impact factor: 15.255