engleski

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

Johanson-Blizzard syndrome (JBS ; 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 locus to chromosome 15q14-21.1, and identified mutations, mostly truncating ones, in the UBR1 gene in 12 unrelated JBS families. 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 residues2-5. Pancreas of JBS patients did not express UBR1, and exhibited intrauterine-onset destructive pancreatitis. We also show that UBR1– /– mice, whose previously reported phenotypes include reduced weight and behavioural abnormalities6, 7, have 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.

Johanson-Blizzard syndrome; pancreatic insufficiency; nasal wing aplasia

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