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American Physiological Society (APS) Releases Highlights from It's Peer Reviewed Journals
A BABY STEP FORWARD IN UNDERSTANDING NEWBORN LIVER DISEASECloning of A 200 Million Year Old Evolutionary Relative May Shed Light on Liver Disease in Newborns
Summary: Bile secretion is a fundamental function of the liver of all vertebrates. The Bile Salt Export Pump (BSEP) is the major thoroughfare for excreting bile salts from the body and is responsible for production of bile flow. Mutations in the human BSEP result in a form of liver disease called progressive intrahepatic cholestasis, or PFIC Type II. PFIC Type II is characterized by persistent neonatal impaired bile flow, aspects of neonatal hepatitis, and subsequent cirrhosis of the liver caused by obstruction or infection. This study presents evidence that the BSEP evolved early in vertebrate evolution and that its functional properties have remained essentially unchanged despite 200 million years of evolution.
Methodology: To determine the evolutionary origin and structure-function relationship of the human BSEP, a full-length clone of a marine skate (Raja erinacea), a 200 million year old vertebrate that shares 68.5 percent of the identity of the human BSEP, was examined. Shi-Ying Cai, Lin Wang, and James L. Boyer of the Yale University School of Medicine, along with Nazzareno Ballatori of the University of Rochester School of Medicine, cloned DNA from a skate liver BSEP (sBSEP). The clone was subjected to Northern blot analysis, and comparisons made in Sf9cells.
Results: The researchers found that the sequences at the site of published mutations in human BSEP were conserved in sBSEP. When two of these mutations were introduced into the sBSEP DNA, a defective expression of the Sf9 cells occurred.
Conclusions: These findings suggest that mutations in human BSEP that result in PFIC-II during infancy might reside in sequences common to sBSEP. Moreover, as 32 percent of the sBSEP sequence is not conserved in human BSEP, and functional studies suggest that sBSEP and mammal BSEPs have identical properties, it is likely that the non-conserved sequences may not be essential for targeting. The possibility that sBSEP is misfolded and prone to degradation is also suggested and a comparative functional genomics approach should be considered.
Source: American Journal of Physiology: Gastrointestinal and Liver Physiology, August 2001
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The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health.The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.
Editor's Note: For the full text of the summaries cited above, or to set up an interview with a lead investigator, please contact Donna Krupa at 703.527.7357 (direct dial), 703.967.2751 (cell) or [email protected].
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