Tiny change in checkpoint protein hastens onset of liver failure in genetic disease

HOUSTON -- (April 28, 2009) -- A single change in the genetic code for a checkpoint enzyme reduces its activity in the cell and results in rapid and early liver failure in children born with alpha-1 antitrypsin deficiency – an inherited disorder that can cause serious lung disease in adults and liver failure in infants, children, and adults, said researchers from Baylor College of Medicine and the University of Florida in a recent report in the journal Hepatology.

People born with a defective gene for alpha-1 antitrypsin do not make a form of the protein that can protect the lungs because it is inappropriately retained in the liver. Some people with the deficiency also have liver disease, but the age at which it occurs varies. In this study, Dr. Richard Sifers, associate professor of pathology at BCM, and his colleagues, identify a particular mutation in the gene for a checkpoint enzyme called ER mannosidase I. This mutation leads to early liver failure, and without a transplant, many such infants die.

Protein folding

In some people who have a variant of the gene called "Z," researchers know that the alpha-1 antitrypsin protein gets made but in a form that does not fold properly. That causes it to accumulate in the liver.

Usually, the mannosidase molecule removes mannose from the protein to mark it for degradation and removal from the liver. However, in collaboration with the BCM Human Genome Sequencing Center, Sifers and his colleagues indentified a mutation in the ER mannosidase I gene that causes the translation of genetic information into a protein to be reduced, slowing the degradation and removal of the defective alpha-1 antitrypsin protein and resulting in liver disease.

"The onset of this genetic disease is regulated by a protein quality control factor that occurs far downstream (from the cell cycle)," said Sifers.

Genetic mishaps

In this case, infants who develop this serious liver disease have had two unlucky genetic mishaps. They are born with a defective alpha-1 antitrypsin gene and a defect in the mannosidase gene as well.

Sifers said the finding points to the importance of protein folding in disease.

"If biology can be compared to a baseball game, then the genes are analogous to the roster. However, the proteins are analogous to the players. You can read the roster all you want, but you have to watch the players and see how they operate in order to understand the game. If their play is defective, then you lose the game," he said.

Others who took part in this research include Shujuan Pan, Lu Huang, John McPherson, Donna Muzny and Richard Gibbs, all of BCM, and Farshid Rouhani and Mark Brantly of the University of Florida at Gainesville.

Funding for this research came from the National Institutes of Health, the Fernandez Liver Initiative and the Alpha-1 Foundation.

An abstract of the article can be found at http://www3.interscience.wiley.com/journal/122266405/abstract.

A preceding article in the Journal of Cell Science by Sifers and Daniel J. Termine of BCM and Kelley W. Moremen of the University of Georgia in Athens describes the activity of ER mannosidase I as a checkpoint protein that regulates the degradation of misfolded proteins. Funding for this work came form the National Institutes of Health and the Alpha-1 Foundation.

A summary of this article can be found here.

For more information on basic science research at Baylor College of Medicine, please go to www.bcm.edu/fromthelab.