Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.
Brain
; 144(9): 2659-2669, 2021 10 22.
Article
en En
| MEDLINE
| ID: mdl-34415322
ABSTRACT
Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Variación Genética
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Antígenos de Histocompatibilidad Menor
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Fosfotransferasas (Aceptor de Grupo Alcohol)
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Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias
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Alelos
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Trastornos del Neurodesarrollo
Límite:
Adolescent
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Adult
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Child
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Child, preschool
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Female
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Humans
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Infant
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Male
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Newborn
Idioma:
En
Revista:
Brain
Año:
2021
Tipo del documento:
Article
País de afiliación:
España