title: Disease-associated variants of microsomal retinol dehydrogenase 12 (RDH12) are degraded at mutant-specific rates.
abstract: Mutations in retinol dehydrogenase 12 (RDH12) cause severe retinal degeneration. However, some of the disease-associated RDH12 mutants retain significant catalytic activity, indicating the existence of additional pathophysiological mechanisms. This study demonstrates that the catalytically active T49M and I51N mutants undergo accelerated degradation, which results in their reduced cellular levels. Inhibition of proteasome leads to significant accumulation of ubiquitylated T49M and I51N. Furthermore, the degree of ubiquitylation strongly correlates with the half-lives of the proteins. These results suggest that the accelerated degradation of RDH12 mutants by the ubiquitin-proteasome system contributes to the pathophysiology and phenotypic variability associated with mutations in the RDH12 gene.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Schools of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Seung-Ah
authors.initials: SA
authors.lastname: Lee
authors.forename: Olga V
authors.initials: OV
authors.lastname: Belyaeva
authors.forename: Natalia Y
authors.initials: NY
authors.lastname: Kedishvili
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008861:Microsomes / Q000201:enzymology*; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D025801:Ubiquitin; D000429:Alcohol Oxidoreductases; C489649:RDH12 protein, human; D046988:Proteasome Endopeptidase Complex