What is pathogenicity? Structural vulnerabilities lead to distinct phenotypes in a membrane protein, ATP1A3
- 1Mass General Hospital
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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BibTeX
@misc{sweadner2026what,
title = {{What is pathogenicity? Structural vulnerabilities lead to distinct phenotypes in a membrane protein, ATP1A3}},
author = {K. J. Sweadner and L. J. Ozelius and A. Domingo and K. Mangkalaphiban and I. U. Haq and A. Brashear and E. Arystarkhova},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.13.758912},
url = {https://www.biorxiv.org/content/10.64898/2026.10.13.758912v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - What is pathogenicity? Structural vulnerabilities lead to distinct phenotypes in a membrane protein, ATP1A3
AU - K. J. Sweadner
AU - L. J. Ozelius
AU - A. Domingo
AU - K. Mangkalaphiban
AU - I. U. Haq
AU - A. Brashear
AU - E. Arystarkhova
PY - 2026
DA - 2026/10/13
PB - bioRxiv
DO - 10.64898/2026.10.13.758912
UR - https://www.biorxiv.org/content/10.64898/2026.10.13.758912v1
AB - 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.
ER -