Abstract

Johanson-Blizzard syndrome (JBS; OMIM 243800) is an autosomal recessive multisystem disorder of which the most prominent characteristic is exocrine pancreatic insufficiency. To determine the molecular basis of JBS, we mapped the disease to 15q14-21.1, using a genome-wide linkage scan. We identified truncating mutations in the gene UBR1 in 12 unrelated JBS families. UBR1 encodes one of several E3 ubiquitin ligases of the N-end rule pathway, an ubiquitin-dependent proteolytic pathway. Human JBS pancreas at 34 weeks gestation revealed complete lack of UBR1 expression and extensive inflammatory infiltrates. The inflammation-necrosis sequence of pancreatic destruction could be confirmed in two additional patients. When we used a murine knockout model of UBR1 known for growth retardation stool measurements for chymotrypsin and elastase revealed exocrine pancreatic insufficiency to be the cause of malnutrition. In vitro studies on pancreatic acini identified impaired stimulus-secretion-coupling-in the presence of normal enzyme synthesis-as the uderlying mechanism. Experimental pancreatic injury in UBR1 knock outs (caerulein pancreatitis) was followed by significantly greater local and systemic inflammation than in wild type. This suggests a vital function of UBR1 not only in acinar cell signal transduction but also in the defense against pathologic damage. JBS is thus an inflammatory disorder due to an inadequate UBR1 defenses.

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