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Genome Affects Human Forms of “Mad Cow” Disease

By Nancy Touchette

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Mad Cow

Brain tissue infected with prions has a spongy appearance.
Last month’s discovery of the first “mad cow” in the United States has rekindled interest in the weird infectious agent that causes the disease and is raising new questions about how the deadly brain disease is transmitted to humans and which people are likely to develop the disease.

Humans can contract disease, known as variant Creutzfeldt-Jakob disease (vCJD), by eating infected beef. But similar forms of the disease can also be inherited or can arise spontaneously. And a person’s genome can influence susceptibility to either form of disease. Of the people who got mad cow disease by eating tainted meat, all of those who have been tested so far have the same genetic variation.

“We don’t know much about how the disease is transmitted or why only certain people appear susceptible,” says Richard Johnson of Johns Hopkins University in Baltimore, Maryland, who headed a recent Institute of Medicine panel to study mad cow and related diseases. “There are too many questions and not enough answers.”

Mad cow disease is one of several related diseases known as spongiform encephalopathies that can affect several animal species. The disease gets its name from the many holes that perforate brain tissue to give it a spongy appearance in diseased individuals.

The infectious agent that is widely thought to cause disease is the prion, a particle of clumped-up protein. This particle, or clump, is made up mostly or entirely from a misshapen protein, known as the prion protein.

In its normal form, the prion protein is found in a wide variety of tissues throughout the body, including the brain, immune system, blood, gut, and liver, and causes no disease. But mutations in the protein can cause it to fold abnormally and clump up to form infectious prions.

Researchers also believe that new prions can form when a normal prion protein comes into physical contact with an abnormally shaped prion protein. For reasons that are totally mysterious, the bad protein makes the good protein turn bad.

How Humans Develop Prion Disease

Several different forms of prion disease occur in humans and they may be contracted in several ways. The chance of developing a human prion disease in any form is less than one in a million.

About 10 percent of all cases of prion disease are inherited--caused by rare mutations in the gene that cause the prion protein to fold abnormally. So far, scientists have identified about 30 different mutations known to cause disease.

Disease can also occur through infection. Kuru, first discovered in the Fore people of Papua, New Guinea, has been traced to a cannibalistic mourning ritual, in which family and friends eat the brain of the deceased person, to confer a sense of immortality. Mourners can contract the disease if the brain tissue they ingest is infected.

Another form of human disease is caused by surgery with infected instruments or injections with contaminated preparations of growth hormone.

The most recent form of infectious prion disease appears to occur in people who ate beef from infected cows. The risk of developing disease from eating meat is extremely low, however. Hundreds of thousands of cows in the United Kingdom were infected, but only 153 people, nearly all in the U.K. , have developed the disease so far from eating meat.

But researchers don’t know how most cases of CJD arise.

“Some 90 percent of all CJD cases are random and occur sporadically in people with no mutations at all,” says Paul Brown of the National Institutes of Health, who studies human prion diseases. “The cause is entirely unknown.”

Susceptibility may Depend on Genes

The particular form of disease, classified according to the clinical symptoms, age of onset, and pathology, seems to depend on the variations in the sequence of the prion protein.

Some variations in the sequence—the mutations—are rare and always lead to disease. Other variations, known as polymorphisms, don’t cause disease by themselves. Many of the polymorphisms have no known effect, but others can affect the course and nature of disease.

The most important polymorphism leads to the formation of two different protein forms. One form has an amino acid called methionine at the 129th amino acid in the protein sequence. The other form has an amino acid called valine at the same position.

About half of the Caucasian population has one copy each of the methionine and valine forms of the protein. Twelve percent have two valine forms, and the rest have two methionines.

All the people thought to have developed the infectious form of CJD from eating infected meat have the double-methionine form of the prion protein, but no other mutations. This suggests that this particular variation somehow influences susceptibility to disease.

The same variation can also influence the symptoms and course of disease for people who inherit more severe disease-causing mutations. For example, a person who carries a mutation at position 178 in the prion protein and also has methionine at position 129 in the same protein molecule, will develop a form of the disease known as fatal familial insomnia. This disease is characterized by insomnia, seizures, mobility problems, and dementia.

On the other hand, if a person inherits the same mutation at position 178, but also has the double valine variation at position 129, Creutzfeld-Jakob disease occurs. The symptoms of this form of disease include rapidly progressing dementia, depression, irritability, and palsy.

Disease occurs when the normal prion protein (top) changes shape (bottom).
The Mysterious Powers of Folding Prions

Researchers don’t know exactly why different forms of the prion protein can affect susceptibility and the course of disease, but they think it has something to do with the way the prion protein folds and how the variations affect this process.

The normal form of the protein has many helical or spiral-shaped stretches, while the abnormal form has many flat, sheet-like structures. The mutations and polymorphisms associated with the disease are thought to affect the shape of the protein, which may in turn affect how it clumps up and causes damage to the brain.

“Different forms of disease can have different symptoms, according to where the protein initially accumulates,” says Guisueppe Legname at the University of California at San Francisco . “But ultimately it’s the accumulation of prions in the brain that kills.”

In 2002, the number of new cases each year began to decrease. But researchers don’t know whether this means the disease has been contained, or whether the disease has a longer incubation time in people with different forms of the prion protein.

“Only those with two copies of the methionine form of the protein have developed the infectious form of disease,” says Johnson. “That could mean the others are not susceptible, or it could mean that the rest are yet to come.”

Prusiner, S.B. Shattuck Lecture: Neurodegenerative diseases and prions. NEJM 344, 1516-1526 (2001).
P. Gambetti et al. Hereditary Creutzfeldt-Jakob disease and fatal familial insomnia. Clin. Lab. Med. 23, 43-64 (2003).
P. Gambetti et al. Sporadic and familial CJD: Classification and characterization. Br. Med. Bull. 66, 213-239 (2003).

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