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 residues2,3,4,5. 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 abnormalities6,7, 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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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.
The authors declare no competing financial interests.
Pedigrees of JBS families (JBS01-JBS13) included in the study. (PDF 74 kb)
Expression analysis of UBR1 and UBR2 mRNA. (PDF 828 kb)
Two-point lod score analysis for the JBS locus on chromosome 15q14-15q21. (PDF 94 kb)
Exon-flanking primers used for PCR amplification and sequencing of human UBR1. (PDF 101 kb)
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