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'Missteps' Can Spell Liver Failure In Children With Genetic Disease

Posted on: Tuesday, 2 June 2009, 11:51 CDT

Two genetic missteps can put an infant with a genetic defect called alpha-1 antitrypsin deficiency on the road to rapid liver failure, 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. Most have serious lung disease but some also have liver disease. The age at which this problem occurs varies.

Richard N. Sifers Ph.D., associate professor of pathology at BCM, and his colleagues, have identified 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.


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