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Defective Enzyme Degradation in Johanson-Blizzard Syndrome

« Back to Volume 22, Issue 2, June 2006 - Table of Contents

The Johanson-Blizzard syndrome (JBS [OMIM 243800]), names not unfamiliar to GGH readers, is an autosomal recessive disorder characterized by congenital exocrine pancreatic insufficiency, mental retardation, facial abnormalities, and various other malformations. As reported by Zenker et al, an international group has now identified the mutant gene. They started by undertaking a genome-wide linkage scan of 7 families with JBS. Analysis of the consanguineous families revealed a region of homozygosity of 7.5 cM on chromosome 15q14-21.1 containing no obvious candidate genes. By high-throughput DNA sequencing of genomic DNA from JBS patients, they eventually detected mutations in the gene UBR1 in patients from 12 unrelated families. Most of the mutations produced premature translation stop codons and most likely loss-of-function for the gene product.

UBR1 encodes an E3 ubiquitin ligase, which transfers ubiquitin moeties to proteins destined for degradation by cytoplasmic proteosomes. Long chains of ubiquitin serve as molecular signals that direct targeted molecules for degradation. UBR1 was one of the first of many E3 ubiquitin ligases to be identified; each possesses specificity regarding which molecules it ubiquitinates. Interestingly, several E3 ubiquitin ligases have been implicated in genetic disease, ie, UBE3A in Angelman syndrome, parkin in recessive juvenile parkinsonism, and VHL in von Hipple-Lindau disease.

To explore how loss of UBR1—which would be expected to lead to failure to ubiquitinate proteins normally ubiquitinated by UBR1—causes JBS, the investigators focused on the exocrine pancreas, since it is the most consistently affected organ system in JBS. Examination of pancreatic tissue from 2 fetuses and a newborn infant with JBS showed loss of acinar tissue with inflammation that worsened with gestation, suggesting a gradual destruction resembling pancreatitis as the fetus approaches term.

They next turned to UBR1 null mouse model. These mice were viable and fertile, but display reduced weight with a proportionate decrease in both muscle and adipose tissue. Their feces contained reduced amounts of chymotrypsin and elastase, indicating pancreatic exocrine insufficiency. They next documented that compared to controls, exocrine cells cultured as acini-like structures exhibited a marked reduced response to treatment with cholecystokinin, the physiologic secretogogue of the exocrine pancreas. The investigators speculated that levels of pancreatic exocrine proenzymes and/or their derivatives may normally need to be kept in check by proteolytic degradation in proteosomes, and that this fails to occur in JBS. Similarly, they suggested that accumulation of proteins normally targeted for degradation by UBR1 may occur in other tissues and organs affected by JBS.

Zenker M, Mayerle J, Lerch MM, et al. 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;37:1345−1350.

Editor’s Comment

This paper nicely documents not only the mutant gene but also the likely mechanism that accounts for the clinical features of JBS. It should be noted that the biology of ubiquitin has become much more complicated than originally suspected. For example, the number of ubiquitins added to a protein may determine its fate: many ubiquitins (polyubiquitination) usually target molecules to proteosomes, whereas addition of one or a few ubiquitins (monoubiquitination) often targets molecules to lysosomes. Monoubiquitination at multiple sites is responsible for lysosomal targeting and signal termination of many if not most activated receptor tyrosine kinases.

William A. Horton, MD

Last Updated: 2/2/2011