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

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.