title: Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome).
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 retardation. 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.
authors.affiliation: Institute of Human Genetics, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany. mzenker@humgenet.uni-erlangen.de
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.forename: Andreas
authors.initials: A
authors.lastname: Tagariello
authors.forename: Klaus
authors.initials: K
authors.lastname: Zerres
authors.forename: Peter R
authors.initials: PR
authors.lastname: Durie
authors.forename: Matthias
authors.initials: M
authors.lastname: Beier
authors.forename: Georg
authors.initials: G
authors.lastname: Hülskamp
authors.forename: Celina
authors.initials: C
authors.lastname: Guzman
authors.forename: Helga
authors.initials: H
authors.lastname: Rehder
authors.forename: Frits A
authors.initials: FA
authors.lastname: Beemer
authors.forename: Ben
authors.initials: B
authors.lastname: Hamel
authors.forename: Philippe
authors.initials: P
authors.lastname: Vanlieferinghen
authors.forename: Ruth
authors.initials: R
authors.lastname: Gershoni-Baruch
authors.forename: Marta W
authors.initials: MW
authors.lastname: Vieira
authors.forename: Miroslav
authors.initials: M
authors.lastname: Dumic
authors.forename: Ron
authors.initials: R
authors.lastname: Auslender
authors.forename: Vera L
authors.initials: VL
authors.lastname: Gil-da-Silva-Lopes
authors.forename: Simone
authors.initials: S
authors.lastname: Steinlicht
authors.forename: Manfred
authors.initials: M
authors.lastname: Rauh
authors.forename: Stavit A
authors.initials: SA
authors.lastname: Shalev
authors.forename: Christian
authors.initials: C
authors.lastname: Thiel
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.forename: Andreas
authors.initials: A
authors.lastname: Winterpacht
authors.forename: Yong Tae
authors.initials: YT
authors.lastname: Kwon
authors.forename: Alexander
authors.initials: A
authors.lastname: Varshavsky
authors.forename: André
authors.initials: A
authors.lastname: Reis
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D019767:Maxillofacial Abnormalities / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009666:Nose / Q000002:abnormalities; D010179:Pancreas / Q000201:enzymology* / Q000473:pathology; D010182:Pancreatic Diseases / Q000235:genetics* / Q000473:pathology; D013577:Syndrome; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics*
chemical_list: C113474:UBR1 protein, human; D044767:Ubiquitin-Protein Ligases