Molecular Characteristics

The ATP8A2 gene is highly expressed in the retina, brain, spinal cord, and testis. Within the brain, ATP8A2 is expressed in all regions the highest levels have been reported in the cerebellum. This gene encodes for phospholipid-transporting ATPase IB (P4-ATPases subfamily). These proteins participate in the maintenance of a physiological asymmetric distribution of phospholipids across the bilayer membrane (lipid flipping).

In mice, ATP8A2 deficiency induces axonal degeneration and neuronal chromatolysis. Mice homozygous for ATP8A2 variant grow slower, have a reduced lifespan, and develop body tremor, abnormal gait and hind limb clasping reflex indicative of neurological deficits.

Reported ATP8A2 variants causing cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ) are missense, nonsense, splice-site, small deletions and insertions; while gross deletions have been only associated with the phenotype of severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy.

Functional studies in mouse models showed that mutant ATP8A2 displays no flippase activity (phosphatidylserine translocase activity). In cultured cells, ATP8A2 mutants (bearing missense variants associated with CAMRQ) are either poorly expressed, displaying an abnormal subcellular distribution and no ATPase activity, or are normally expressed and distributed in the cell but lack ATPase activity. In both cases, ATP8A2 variants are associated with a loss-of-function mechanism.