What is pathogenicity? Structural vulnerabilities lead to distinct phenotypes in a membrane protein, ATP1A3

Authors

Sweadner, K. J., Ozelius, L. J., Domingo, A., Mangkalaphiban, K., Haq, I. U., Brashear, A., Arystarkhova, E.

Abstract

Distinct protein features of pathogenic variants are illustrated here for a gene with an extraordinarily wide range of neurological syndromes: ATP1A3, the neuronal Na,K-ATPase. Vulnerable structure features produce mechanistically different consequences, from loss or gain of function to maladaptive cell biological responses. Variants in specific structural elements (glycines, prolines, and {beta}-sheets) link severe phenotype to impaired folding during biosynthesis. In contrast, impaired protein-protein interactions may result in brain malformation. Defective RNA transcripts, on the other hand, exhibit a range of benign to severe phenotypes, likely due to efficacy variability in the defensive degradation of aberrant mRNA and protein. Variant interpretation will benefit from understanding structure-specific vulnerabilities.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 16 Oct 2026.

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