A novel missense variant in the ATPase domain of ATP8A2 and review of phenotypic variability of ATP8A2-related disorders caused by missense changes

Abstract

ATPase, class 1, type 8 A, member 2 (ATP8A2) is a P4-ATPase with a critical role in phospholipid translocation across the plasma membrane. Pathogenic variants in ATP8A2 are known to cause cerebellar ataxia, impaired intellectual development, and disequilibrium syndrome 4 (CAMRQ4) which is often associated with encephalopathy, global developmental delay, and severe motor deficits. Here, we present a family with two siblings born from a consanguineous, first-cousin union from Sudan presenting with global developmental delay, intellectual disability, spasticity, ataxia, nystagmus, and thin corpus callosum. Whole exome sequencing revealed a homozygous missense variant in the nucleotide binding domain of ATP8A2 (p.Leu538Pro) that results in near complete loss of protein expression. This is in line with other missense variants in the same domain leading to protein misfolding and loss of ATPase function. In addition, by performing diffusion-weighted imaging, we identified bilateral hyperintensities in the posterior limbs of the internal capsule suggesting possible microstructural changes in axon tracts that had not been appreciated before and could contribute to the sensorimotor deficits in these individuals.

Keywords: ATP8A2; ATPase (Min.5-Max. 8); CAMRQ4; Neurodevelopmental disorder; Rare variants.

Fig. 1

Brain imaging shows internal capsule alteration in both siblings. A. Family pedigree with protein variant inheritance. B-C Brain MRI of P1 shows thinning of the corpus callosum (arrows) in T1-weighted imaging (B) and a moderate enlargement of the lateral ventricles evident in T2-weighted imaging (C). D-E Both siblings (P1 in D and P2 in E) show bilateral hyperintensity in the posterior limbs of the internal capsule (arrowheads) in diffusion-weighted imaging

Fig. 2

Conservation and localization of the p.Leu538Pro (L538P) variant. (A) L538P is located in the nucleotide binding (N) domain. Most previously identified missense variants in ATP8A2 occur in the cytoplasmic N, actuator (A), or phosphorylation (P) catalytic domains (G447A and G447E were not reported clinically but were previously evaluated in functional studies). (B) Alphafold structure of ATP8A2 shows that the L538P mutation is located within an alpha helical region of the nucleotide binding domain (N-domain). (C) This residue is highly conserved within different species of ATP8A2 (Human (Q9NTI2) Bos taurus (C7EXK4), Mus musculus (P98200), Gallus gallus (A0A1D5P6U3), Danio rerio (A0A8M1RFW8) and the yeast homolog DRS2P (P39524) but less conserved in other P4-ATPases that all contain an amino acid with a hydrophobic side chain. D-E Western blot analysis of the mutant construct reveals little if any expression of the L538P variant compared to that of WT ATP8A2 (WT: N = 3; L538P: N = 3)