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Published on: August 24, 2022
Disease-associated variants of microsomal retinol dehydrogenase 12 (RDH12) are degraded at mutant-specific rates
Seung-Ah Lee1, Olga V Belyaeva, Natalia Y Kedishvili
1Department of Biochemistry and Molecular Genetics, Schools of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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.
Insights
Retinol dehydrogenase 12 (RDH12) mutations cause retinal degeneration. Even active mutants degrade faster via the proteasome, explaining disease variability.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Mutations in retinol dehydrogenase 12 (RDH12) are linked to severe retinal degeneration.
- Some RDH12 mutants retain catalytic activity, suggesting other disease mechanisms beyond enzyme function.
Purpose of the Study:
- To investigate the degradation pathways of catalytically active RDH12 mutants.
- To determine the role of the ubiquitin-proteasome system in RDH12 mutant pathophysiology.
Main Methods:
- Expression and analysis of RDH12 mutants (T49M, I51N).
- Assessment of protein degradation rates and cellular levels.
- Ubiquitylation assays and proteasome inhibition studies.
Main Results:
- Catalytically active RDH12 mutants (T49M, I51N) exhibit accelerated degradation.
- Proteasome inhibition leads to accumulation of ubiquitylated T49M and I51N mutants.
- Protein ubiquitylation levels correlate with mutant protein half-lives.
Conclusions:
- Accelerated degradation of RDH12 mutants via the ubiquitin-proteasome system contributes to retinal degeneration.
- This degradation pathway explains phenotypic variability in RDH12-associated retinopathies.
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