A recent article in Science News highlighted a discovery by Richard Seifes, M.D. of Baylor College of Medicine.  Dr. Seifes has discovered the origin of a liver disease that has plagued newborns and babies.

But Dr. Seifes did not stop there. His desire to focus on discovery led him to find a unique cellular process involving the disposal of proteins that are misfolded.

As people age, their chances of acquiring diseases such as Parkinson’s, diabetes, or Alzheimer’s increases. These diseases have one thing in common: they are caused by proteins that are misfolded. Proteins are involved in almost every mechanism in the cell. If their function is disrupted, the results may be devastating.

About Alpha1-antitrypsin (AAT) Deficiency

Dr. Sifers was determined to find out why patients with AAT deficiency exhibit such a widely different response. In addition to AAT deficiency, Alzheimer’s and other neurological disorders are related to the buildup of proteins that are defective. Some people have the AAT gene plus the “Z” mutation.

Dr. Sifers began his studies of AAT deficiency when he became aware that some people with two copies of the “Z” mutation had experienced lung disease in adulthood while others were found to have liver disease. It also seemed that there was a wide variation in severity.

A Rare Disease

On the other hand, Dr. Sifers noted that the disease could develop in infants and require a transplant in order for the infant or newborn to survive. Seventeen percent of affected newborn who have the AAT-Z gene had a significant liver disease while up to three percent was life-threatening or end-stage.

Dr. Sifer assisted in the development of one of the initial screening tests that would predict the risk of significant liver disorder in a newborn. However, he was still unable to determine the cause of the disorder.

About the Mechanism of the AAT Protein and Z Mutation

The liver produces the AAT protein which travels into the lungs and protects the lungs from damage by other proteins.

The AAT-Z mutation produces proteins that are defective. These defective proteins are not able to fold and leave the liver in order to protect the lungs. This results in lung disorders such as emphysema.

As Dr. Sifer researched the disease, he noticed that AAT-Z was accumulating in the liver rather than being released, indicating a disruption in how the cell disposes of proteins that are misfolded.

Subsequently, Dr. Sifer and his team discovered an enzyme called Man1b1 that causes the destruction of AAT-Z proteins. The discovery brought Dr. Sifer closer to finding the cause of these disorders.

The Cause of Liver Disease in Infants

In 2009, Dr. Sifers and his team analyzed the liver tissue samples from infants and children over the age of two who had end-stage liver disease and had received liver transplants.

Their conclusion was that Man1b1, at lower levels, would have a negative impact on the liver’s ability to handle the accumulation of the misfolded AAT-Z.

This resulted in a markedly increased accumulation of misfolded AAT-Z protein accumulation and accelerated rates of liver failure.

Dr. Sifers expressed satisfaction that after many years of research, the mystery of liver disease in infants as it relates to AAT deficiency has been solved.

The Mystery Leads to Discovery

As Dr. Sifers and his team continued their studies of Man1b1, they discovered that Man1b1 promoted the destruction of proteins in a separate process completely removed from Dr. Sifer’s first discovery.

He was joined by his associates, Dr. Collette and Dr. Sun. They reported that the enzymatic removal system can be found on the C-terminal side of Man1b1. This is called the “conventional” enzymatic removal system.

On the other hand, the “unconventional” system is found in the N-terminal which is on the opposite side.

The team will be conducting additional studies to determine how these systems work in tandem. For instance, Man1b1 has been associated with HIV and intellectual disability disorders as well as bladder cancer.

Dr. Sifers commented that these studies present evidence that research into rare diseases will lead to solving issues in common disorders.