PI4KA, also known as Phosphatidylinositol 4-kinase IIIα, is an essential lipid kinase. It generates phosphatidylinositol 4-phosphate (PI4P) at the plasma membrane, which is crucial for lipid transport and regulating PLC and PI3K signalling pathways [5]. PI4KA exists in multi-protein complexes, and its regulation is vital as misregulation can lead to various human diseases [1].

Mutations in PI4KA have been associated with a wide range of disorders. Biallelic sequence alterations in humans are linked to neurological diseases like hypomyelinating leukodystrophy, and affected individuals may also present with inflammatory bowel disease, multiple intestinal atresia, and combined immunodeficiency [2]. Biallelic mutations disrupt B-cell metabolism, causing B-cell lymphopenia and hypogammaglobulinemia by altering lipid production, TCA cycle regulation, and increasing endoplasmic reticulum stress [3]. Additionally, biallelic variants can lead to a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy, and high expression of PI4KA in drug-resistant leukemia cells is correlated with poor overall survival, while its depletion sensitizes these cells to chemotherapy [4,6].

In conclusion, PI4KA is essential for generating PI4P at the plasma membrane and regulating key signalling pathways. Studies on PI4KA-related mutations in humans have revealed its significant role in neurological, intestinal, immunological diseases, and leukemia chemoresistance. Understanding PI4KA function through these genetic models provides insights into disease mechanisms and potential therapeutic strategies.