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Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome)

Zenker, Martin and Varshavsky, Alexander (2005) Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome). Nature Genetics, 37 (12). pp. 1345-1350. ISSN 1061-4036. https://resolver.caltech.edu/CaltechAUTHORS:20150319-070411230

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Abstract

Johanson-Blizzard syndrome (OMIM 243800) is an autosomal recessive disorder that includes congenital exocrine pancreatic insufficiency, multiple malformations such as nasal wing aplasia, and frequent mental retardation1. We mapped the disease-associated locus to chromosome 15q14–21.1 and identified mutations, mostly truncating ones, in the gene UBR1 in 12 unrelated families with Johanson-Blizzard syndrome. UBR1 encodes one of at least four functionally overlapping E3 ubiquitin ligases of the N-end rule pathway, a conserved proteolytic system whose substrates include proteins with destabilizing N-terminal residues. Pancreas of individuals with Johanson-Blizzard syndrome did not express UBR1 and had intrauterine-onset destructive pancreatitis. In addition, we found that Ubr1-/- mice, whose previously reported phenotypes include reduced weight and behavioral abnormalities, had an exocrine pancreatic insufficiency, with impaired stimulus-secretion coupling and increased susceptibility to pancreatic injury. Our findings indicate that deficiency of UBR1 perturbs the pancreas' acinar cells and other organs, presumably owing to metabolic stabilization of specific substrates of the N-end rule pathway.


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http://dx.doi.org/10.1038/ng1681 DOIArticle
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http://www.nature.com/ng/journal/v37/n12/suppinfo/ng1681_S1.htmlPublisherSupplementary Information
http://dx.doi.org/10.1038/ng0206-265 DOICorrigendum
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ORCID:
AuthorORCID
Varshavsky, Alexander0000-0002-4011-258X
Additional Information:© 2005 Nature Publishing Group. Received 28 July; accepted 8 September; published online 20 November 2005. We thank all participating families for making this study possible; A. Diem, E. Dazert and S. Balk for technical assistance; and G. Nürnberg for lod score calculations. This research was supported by grants from the Marohn Foundation of the University of Erlangen-Nuremberg and from the German Research Foundation to M.Z. and A.R., from the German Research Foundation and the Deutsche Krebshilfe to M.M.L. and J.M. and from the US National Institutes of Health and the Ellison Medical Foundation to A.V. and Y.T.K.
Funders:
Funding AgencyGrant Number
University of Erlangen-Nuremberg Marohn FoundationUNSPECIFIED
Deutsche Forschungsgemeinschaft (DFG)UNSPECIFIED
Deutsche KrebshilfeUNSPECIFIED
NIHUNSPECIFIED
Ellison Medical FoundationUNSPECIFIED
Issue or Number:12
Record Number:CaltechAUTHORS:20150319-070411230
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150319-070411230
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:55908
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:19 Mar 2015 16:18
Last Modified:25 Nov 2020 20:33

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