Genotype-structure-phenotype relationships diverge in paralogs ATP1A1, ATP1A2, and ATP1A3.

ABSTRACT:

Objective

We tested the assumption that closely related genes should have similar pathogenic variants by analyzing >200 pathogenic variants in a gene family with high neurologic impact and high sequence identity, the Na,K-ATPases ATP1A1, ATP1A2, and ATP1A3.

Methods

Data sets of disease-associated variants were compared. Their equivalent positions in protein crystal structures were used for insights into pathogenicity and correlated with the phenotype and conservation of homology.

Results

Relatively few mutations affected the corresponding amino acids in 2 genes. In the membrane domain of ATP1A3 (primarily expressed in neurons), variants producing milder neurologic phenotypes had different structural positions than variants producing severe

SUBMITTER: Sweadner KJ 

PROVIDER: S-EPMC6384024 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature