Phenylketonuria (PKU) is an inherited disease characterized by progressive mental retardation and seizures because the individual is deficient in the protein PAH. Most of the genetic mutations that cause PKU do so because the PAH protein that is generated by the mutated gene is not stable enough to function. New data, generated by Aurora Martinez and colleagues, at the University of Bergen, Norway, suggest that it might be possible to stabilize the mutated PAH protein in individuals with PKU such that it can function normally.
In the study, a high-throughput screen for small molecules that stabilized mutated forms of the PAH protein found in individuals with PKU identified four potential candidates. Two of these molecules were analyzed in more detail and shown to stabilize both normal and mutated PAH in their functional conformation. In addition, these molecules increased the activity and amount of normal PAH and mutated PAH expressed in human cells in vitro and increased PAH activity in the liver of mice. The authors therefore suggest that molecules that stabilize PAH (which are known as chaperones) might provide a new approach to the treatment of individuals with PKU.
TITLE: Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria
AUTHOR CONTACT:
Aurora Martinez
University of Bergen, Bergen, Norway.
Phone: 47-55-58-64-27; Fax: 47-55-58-63-60; E-mail: aurora.martinez@biomed.uib.no.
Javier Sancho
Universidad de Zaragoza, Zaragoza, Spain.
Phone: 00-34-976-76-1286; Fax: 00-34-976-76-2123; E-mail: jsancho@unizar.es.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34355
Journal
Journal of Clinical Investigation