Ionic leakage underlies a gain-of-function effect of dominant disease mutations affecting diverse P-type ATPases

Nat Genet. 2014 Feb;46(2):144-51. doi: 10.1038/ng.2850. Epub 2013 Dec 15.


Type II P-type ATPases (PAIIs) constitute a family of conserved proteins that actively generate ionic gradients across membranes. Mutations in genes encoding PAIIs can cause heritable dominant diseases, with suggested etiology of haploinsufficiency. Using a Drosophila melanogaster genetic screen, we identified a dominant mutation altering the PAII member sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA). This mutation conferred temperature-sensitive uncoordination in a gain-of-function manner. We established that this gain-of-function phenotype is linked to dominant disease-causing mutations affecting various human PAIIs. We further found that heterologous expression of mutant PAIIs elicited ion leakage that was exacerbated at elevated temperatures. Therefore, these dominant mutations result in ionic leakage and render PAIIs susceptible to deleterious effects from elevated temperatures. Accordingly, it was recently reported that missense mutations affecting the Na(+)/K(+) ATPase can elicit ionic leakage. We propose that ionic leakage is a pervasive gain-of-function mechanism that can underlie a variety of dominant PAII-related diseases.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Ataxia / genetics*
  • Base Sequence
  • Cloning, Molecular
  • Crosses, Genetic
  • Drosophila Proteins / genetics
  • Drosophila melanogaster / enzymology*
  • Drosophila melanogaster / metabolism
  • Genes, Dominant / genetics
  • Humans
  • Hydrogen-Ion Concentration
  • Ion Transport / genetics
  • Models, Molecular*
  • Molecular Sequence Data
  • Mutagenesis
  • Mutation, Missense / genetics
  • Phenotype*
  • Protein Conformation*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Sequence Analysis, DNA
  • Sodium-Potassium-Exchanging ATPase / genetics*
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Temperature


  • Drosophila Proteins
  • UNC protein, Drosophila
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Sodium-Potassium-Exchanging ATPase