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bioRxiv · 10.64898/2026.10.13.758912

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

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

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Sweadner, K. J., Ozelius, L. J., Domingo, A., Mangkalaphiban, K., Haq, I. U., Brashear, A., Arystarkhova, E.. 2026-10-15. What is pathogenicity? Structural vulnerabilities lead to distinct phenotypes in a membrane protein, ATP1A3. https://doi.org/10.64898/2026.10.13.758912

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