Nature Genetics 37, 1345 - 1350 (2005)
Published online: 20 November 2005; | doi:10.1038/ng1681
There is a Corrigenda (February 2006) associated with this Correspondence.
Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome)Martin Zenker1, 20, Julia Mayerle2, 20, Markus M Lerch2, Andreas Tagariello1, Klaus Zerres3, Peter R Durie4, Matthias Beier2, Georg Hülskamp5, Celina Guzman6, Helga Rehder7, Frits A Beemer8, Ben Hamel9, Philippe Vanlieferinghen10, Ruth Gershoni-Baruch11, Marta W Vieira12, Miroslav Dumic13, Ron Auslender14, Vera L Gil-da-Silva-Lopes15, Simone Steinlicht1, Manfred Rauh16, Stavit A Shalev17, Christian Thiel1, Andreas Winterpacht1, Yong Tae Kwon18, Alexander Varshavsky19
& André Reis11
Institute of Human Genetics, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany. 2
Department of Gastroenterology, Endocrinology and Nutrition, Ernst-Moritz-Arndt-University of Greifswald, Germany. 3
Institute of Human Genetics, University of Aachen, Germany. 4
Programme in Integrative Biology, the Research Institute, the Hospital for Sick Children, Toronto, Canada. 5
Department of Pediatrics, University of Muenster, Germany. 6
National Children's Hospital, University of Costa Rica, Costa Rica. 7
Department of Human Genetics, KIMCL, Medical University Vienna, Austria. 8
Department of Medical Genetics, University Utrecht, The Netherlands. 9
Department of Human Genetics, Radboud University Nijmegen Medical Centre, The Netherlands. 10
Department of Pediatrics, Unit of Neonatology, Hotel-Dieu, CHU, Clermont-Ferrand, France. 11
Department of Genetics, Rambam Medical Center, Haifa, Israel. 12
Department of Medical Genetics, Catholic University of São Paolo, Brazil. 13
Children's Hospital Rebro, University of Zagreb, Croatia. 14
Department of Obstetrics and Gynecology, Carmel Medical Center, Haifa, Israel. 15
Department of Medical Genetics, State University of Campinas, São Paulo, Brazil. 16
University Children's Hospital, Erlangen, Germany. 17
Genetic Institute, Ha'Emek Medical Center, Afula, Israel. 18
Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pennsylvania, USA. 19
Division of Biology, California Institute of Technology, Pasadena, California, USA. 20
These authors contributed equally to this work.
Correspondence should be addressed to Martin Zenker mzenker@humgenet.uni-erlangen.de 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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