Biallelic PI4KA variants cause neurological, intestinal and immunological disease.
Brain
; 144(12): 3597-3610, 2021 12 31.
Article
em En
| MEDLINE
| ID: mdl-34415310
ABSTRACT
Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM600286) 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antígenos de Histocompatibilidade Menor
/
Fosfotransferases (Aceptor do Grupo Álcool)
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Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central
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Doenças da Imunodeficiência Primária
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Atresia Intestinal
Tipo de estudo:
Prognostic_studies
Limite:
Female
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Humans
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Male
Idioma:
En
Revista:
Brain
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Reino Unido