Biallelic PI4KA variants cause neurological, intestinal and immunological disease

Claire G. Salter, Yiying Cai, Bernice Lo, Guy Helman, Henry Taylor, Amber Mccartney, Joseph S. Leslie, Andrea Accogli, Federico Zara, Monica Traverso, James Fasham, Joshua A. Lees, Matteo P. Ferla, Barry A. Chioza, Olivia Wenger, Ethan Scott, Harold E. Cross, Joanna Crawford, Ilka Warshawsky, Matthew KeislingDimitris Agamanolis, Catherine Ward Melver, Helen Cox, Mamoun Elawad, Tamas Marton, Matthew N. Wakeling, Dirk Holzinger, Stephan Tippelt, Martin Munteanu, Deyana Valcheva, Christin Deal, Sara Van Meerbeke, Catherine Walsh Vockley, Manish J. Butte, Utkucan Acar, Marjo S. Van Der Knaap, G. Christoph Korenke, Urania Kotzaeridou, Tamas Balla, Cas Simons, Holm H. Uhlig, Andrew H. Crosby, Pietro De Camilli, Nicole I. Wolf, Emma L. Baple

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3597-3610
Number of pages14
Issue number12
StatePublished - Dec 1 2021


  • FAM126A
  • PI4KA
  • TTC7A
  • hypomyelinating leukodystrophy
  • multiple intestinal atresia

ASJC Scopus subject areas

  • Clinical Neurology


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