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

HOUSTON -- 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.

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