Novel variants in critical domains of ATP8A2 and expansion of clinical spectrum

ATP8A2 is a P4‐ATPase that flips phosphatidylserine across membranes to generate and maintain transmembrane phospholipid asymmetry. Loss‐of‐function variants cause severe neurodegenerative and developmental disorders. We have identified three ATP8A2 variants in unrelated Iranian families that cause intellectual disability, dystonia, below‐average head circumference, mild optic atrophy, and developmental delay. Additionally, all the affected individuals displayed tooth abnormalities associated with defects in teeth development. Two variants (p.Asp825His and p.Met438Val) reside in critical functional domains of ATP8A2. These variants express at very low levels and lack ATPase activity. Inhibitor studies indicate that these variants are misfolded and degraded by the cellular proteasome. We conclude that Asp825, which coordinates with the Mg2+ ion within the ATP binding site, and Met438 are essential for the proper folding of ATP8A2 into a functional flippase. We also provide evidence on the association of tooth abnormalities with defects in ATP8A2, thereby expanding the clinical spectrum of the associated disease. We report three unrelated patients with variants in ATP8A2 gene. Our data provide clear evidence that the Asp825 which coordinates to the Mg2+ ion within the ATP binding site and Met438 are essential for the proper folding of ATP8A2 into a functional flippase. We also expand the clinical spectrum of ATP8A2 phenotypes by reporting different tooth abnormalities ranging from dental malalignment to severe tooth agenesis suggesting that disruption of ATP8A2 flippase activity interferes with teeth development.