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

Nat Genet. 2005 Dec;37(12):1345-50. doi: 10.1038/ng1681. Epub 2005 Nov 20.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Amino Acid Sequence
  • Animals
  • Chromosome Mapping
  • Chromosomes, Human, Pair 15 / genetics
  • Humans
  • Intellectual Disability / genetics*
  • Maxillofacial Abnormalities / genetics
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Nose / abnormalities
  • Pancreas / enzymology*
  • Pancreas / pathology
  • Pancreatic Diseases / genetics*
  • Pancreatic Diseases / pathology
  • Syndrome
  • Ubiquitin-Protein Ligases / deficiency*
  • Ubiquitin-Protein Ligases / genetics*


  • UBR1 protein, human
  • Ubiquitin-Protein Ligases

Associated data

  • GENBANK/AAB42328
  • GENBANK/AAC40165
  • GENBANK/AAF48687
  • GENBANK/AAH64512
  • GENBANK/AAL32103
  • OMIM/243800
  • RefSeq/NM_174916
  • RefSeq/NP_011700
  • RefSeq/XP_421165