Molecular Characteristics

Most of the identified patients had missense variants, which were mostly clustered near the active site of PI4KA in the catalytic and “cradle” domains. The patients harboring one loss-of-function variant were compound heterozygotes with a missense or in-frame variant, with no patients harboring two loss-of-function variants.

Pathophysiologic mechanisms
Molecular modelling studies defined the likely disease mechanism as impaired PI4KIIIα catalytic function and/or differential impact on complex formation with TTC7A or TTC7B.

PI4KA malfunction lead to disturbances in inositol phospholipids metabolism. These lipids are important in processes such as actin remodeling and oligodendrocyte membrane polarization and membrane lipidome, which are essential for myelination.

Polarization is also essential for bowel epithelial lumen formation.

Polyphosphoinositides act as second messengers activating downstream signaling cascades involved in numerous immune cell functions from cell survival and growth to cell adhesion and migration.