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

Lee, Seung-Ah; Belyaeva, Olga V.; Kedishvili, Natalia Y.

doi:10.1016/j.febslet.2009.12.009

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Volume 584, Issue 3 , Pages 507-510, 5 February 2010

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

Edited by Noboru Mizushima

Department of Biochemistry and Molecular Genetics, Schools of Medicine and Dentistry, University of Alabama at Birmingham, 720 20th Street South, 440B Kaul Genetics Building, Birmingham, AL 35294, USA

Received 13 November 2009; received in revised form 1 December 2009; accepted 5 December 2009. published online 14 December 2009.

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.

Structured summary

MINT-7383581, MINT-7383598: RDH12 (uniprotkb:Q96NR8) physically interacts (MI:0915) with ubiquitin (uniprotkb:P62988) by anti tag coimmunoprecipitation (MI:0007)

Abbreviations: RDH, retinol dehydrogenase, HA, heme agglutinin

Keywords: Dehydrogenase, Retinol, Retinaldehyde, Mutation, Disease, Degradation