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 Keisling; Dimitris 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

doi:https://doi.org/10.1093/brain/awab313

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 journal › Article › Academic › peer-review

14 Citations (Scopus)

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.

Original language	English
Pages (from-to)	3597-3610
Journal	Brain
Volume	144
Issue number	12
Early online date	20 Aug 2021
DOIs	https://doi.org/10.1093/brain/awab313
Publication status	Published - 31 Dec 2021

Access to Document

https://doi.org/10.1093/brain/awab313

Cite this

Salter, C. G., Cai, Y., Lo, B., Helman, G., Taylor, H., McCartney, A., Leslie, J. S., Accogli, A., Zara, F., Traverso, M., Fasham, J., Lees, J. A., Ferla, M. P., Chioza, B. A., Wenger, O., Scott, E., Cross, H. E., Crawford, J., Warshawsky, I., ... Baple, E. L. (2021). Biallelic PI4KA variants cause neurological, intestinal and immunological disease. Brain, 144(12), 3597-3610. https://doi.org/10.1093/brain/awab313

@article{5cafdd25482147baa230399a19bbc4a6,

title = "Biallelic PI4KA variants cause neurological, intestinal and immunological disease",

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.",

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

year = "2021",

month = dec,

day = "31",

doi = "https://doi.org/10.1093/brain/awab313",

language = "English",

volume = "144",

pages = "3597--3610",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

number = "12",

}

Salter, CG, Cai, Y, Lo, B, Helman, G, Taylor, H, McCartney, A, Leslie, JS, Accogli, A, Zara, F, Traverso, M, Fasham, J, Lees, JA, Ferla, MP, Chioza, BA, Wenger, O, Scott, E, Cross, HE, Crawford, J, Warshawsky, I, Keisling, M, Agamanolis, D, Ward Melver, C, Cox, H, Elawad, M, Marton, T, Wakeling, MN, Holzinger, D, Tippelt, S, Munteanu, M, Valcheva, D, Deal, C, van Meerbeke, S, Walsh Vockley, C, Butte, MJ, Acar, U, van der Knaap, MS, Korenke, GC, Kotzaeridou, U, Balla, T, Simons, C, Uhlig, HH, Crosby, AH, de Camilli, P, Wolf, NI & Baple, EL 2021, 'Biallelic PI4KA variants cause neurological, intestinal and immunological disease', Brain, vol. 144, no. 12, pp. 3597-3610. https://doi.org/10.1093/brain/awab313

TY - JOUR

T1 - Biallelic PI4KA variants cause neurological, intestinal and immunological disease

AU - Salter, Claire G.

AU - Cai, Yiying

AU - Lo, Bernice

AU - Helman, Guy

AU - Taylor, Henry

AU - McCartney, Amber

AU - Leslie, Joseph S.

AU - Accogli, Andrea

AU - Zara, Federico

AU - Traverso, Monica

AU - Fasham, James

AU - Lees, Joshua A.

AU - Ferla, Matteo P.

AU - Chioza, Barry A.

AU - Wenger, Olivia

AU - Scott, Ethan

AU - Cross, Harold E.

AU - Crawford, Joanna

AU - Warshawsky, Ilka

AU - Keisling, Matthew

AU - Agamanolis, Dimitris

AU - Ward Melver, Catherine

AU - Cox, Helen

AU - Elawad, Mamoun

AU - Marton, Tamas

AU - Wakeling, Matthew N.

AU - Holzinger, Dirk

AU - Tippelt, Stephan

AU - Munteanu, Martin

AU - Valcheva, Deyana

AU - Deal, Christin

AU - van Meerbeke, Sara

AU - Walsh Vockley, Catherine

AU - Butte, Manish J.

AU - Acar, Utkucan

AU - van der Knaap, Marjo S.

AU - Korenke, G. Christoph

AU - Kotzaeridou, Urania

AU - Balla, Tamas

AU - Simons, Cas

AU - Uhlig, Holm H.

AU - Crosby, Andrew H.

AU - de Camilli, Pietro

AU - Wolf, Nicole I.

AU - Baple, Emma L.

PY - 2021/12/31

Y1 - 2021/12/31

N2 - 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.

AB - 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.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85125016289&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/34415310

U2 - https://doi.org/10.1093/brain/awab313

DO - https://doi.org/10.1093/brain/awab313

M3 - Article

C2 - 34415310

SN - 0006-8950

VL - 144

SP - 3597

EP - 3610

JO - Brain

JF - Brain

IS - 12

ER -

Biallelic PI4KA variants cause neurological, intestinal and immunological disease

Abstract

Access to Document

Other files and links

Cite this