title: Ionic leakage underlies a gain-of-function effect of dominant disease mutations affecting diverse P-type ATPases.
abstract: 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.
authors: Department of Molecular and Cellular Neuroscience, Scripps Research Institute, La Jolla, California, USA.
authors: Maki
authors: M
authors: Kaneko
authors: Department of Molecular and Cellular Neuroscience, Scripps Research Institute, La Jolla, California, USA.
authors: Bela S
authors: BS
authors: Desai
authors: Department of Molecular and Cellular Neuroscience, Scripps Research Institute, La Jolla, California, USA.
authors: Boaz
authors: B
authors: Cook
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001259:Ataxia / Q000235:genetics*; D001483:Base Sequence; D003001:Cloning, Molecular; D003433:Crosses, Genetic; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000378:metabolism; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017136:Ion Transport / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D011487:Protein Conformation; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics* / Q000378:metabolism; D013696:Temperature
chemical_list: D029721:Drosophila Proteins; C488771:UNC protein, Drosophila; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase