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Published September 13, 2011 | Published
Journal Article Open

Ubiquitin Ligases of the N-End Rule Pathway: Assessment of Mutations in UBR1 That Cause the Johanson-Blizzard Syndrome


Background: Johanson-Blizzard syndrome (JBS; OMIM 243800) is an autosomal recessive disorder that includes congenital exocrine pancreatic insufficiency, facial dysmorphism with the characteristic nasal wing hypoplasia, multiple malformations, and frequent mental retardation. Our previous work has shown that JBS is caused by mutations in human UBR1, which encodes one of the E3 ubiquitin ligases of the N-end rule pathway. The N-end rule relates the regulation of the in vivo half-life of a protein to the identity of its N-terminal residue. One class of degradation signals (degrons) recognized by UBR1 are destabilizing N-terminal residues of protein substrates. Methodology/Principal Findings: Most JBS-causing alterations of UBR1 are nonsense, frameshift or splice-site mutations that abolish UBR1 activity. We report here missense mutations of human UBR1 in patients with milder variants of JBS. These single-residue changes, including a previously reported missense mutation, involve positions in the RING-H2 and UBR domains of UBR1 that are conserved among eukaryotes. Taking advantage of this conservation, we constructed alleles of the yeast Saccharomyces cerevisiae UBR1 that were counterparts of missense JBS-UBR1 alleles. Among these yeast Ubr1 mutants, one of them (H160R) was inactive in yeast-based activity assays, the other one (Q1224E) had a detectable but weak activity, and the third one (V146L) exhibited a decreased but significant activity, in agreement with manifestations of JBS in the corresponding JBS patients. Conclusions/Significance: These results, made possible by modeling defects of a human ubiquitin ligase in its yeast counterpart, verified and confirmed the relevance of specific missense UBR1 alleles to JBS, and suggested that a residual activity of a missense allele is causally associated with milder variants of JBS.

Additional Information

© 2011 Hwang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received July 26, 2011; Accepted August 19, 2011. Published online 2011 September 13. This work was supported by the German Research Foundation (DFG) grant ZE 5242-3 to M.Z. and grant MA 4115/1-3 to J.M.; by the Korea Research Foundation grant 2008-313-C00521 to H.K.S.; by a grant from the March of Dimes Foundation to A.V.; and by the National Institutes of Health (NIH) grants GM031530 and DK039520 to A.V. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Editor: Alfred Nordheim, University of Tuebingen, Germany. We thank patients and their families for participating in this study, Angelika Diem (University of Erlangen, Germany) for excellent technical assistance, and Brandon Wadas (California Institute of Technology, USA) for helpful comments on the manuscript. Author Contributions: Conceived and designed the experiments: CSH MS MCA HB APA JM HKS AV MZ. Performed the experiments: CSH MS OB MCA HB APA. Analyzed the data: CSH MS MCA HB APA JM HKS AV MZ. Contributed reagents/materials/analysis tools: CSH MS MCA HB APA JM HKS AV MZ. Wrote the paper: CSH AV MZ.

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