Disease-associated variants of microsomal retinol dehydrogenase 12 (RDH12) are degraded at mutant-specific rates

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 T4...

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Bibliographic Details
Published in:FEBS letters 2010-02, Vol.584 (3), p.507-510
Main Authors: Lee, Seung-Ah, Belyaeva, Olga V., Kedishvili, Natalia Y.
Format: Article
Language:English
Subjects:
Alcohol Oxidoreductases - genetics
Alcohol Oxidoreductases - metabolism
Blotting, Western
Cell Line
Degradation
Dehydrogenase
Disease
heme agglutinin
Humans
Lysosomes - metabolism
Microsomes - enzymology
Mutation
Proteasome Endopeptidase Complex - metabolism
RDH
Retinaldehyde
Retinol
retinol dehydrogenase
Ubiquitin - metabolism
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Summary: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. MINT-7383581, MINT-7383598: RDH12 (uniprotkb:Q96NR8) physically interacts (MI:0915) with ubiquitin (uniprotkb:P62988) by anti tag coimmunoprecipitation (MI:0007)
ISSN:0014-5793
1873-3468
DOI:10.1016/j.febslet.2009.12.009