Scientists have identified the genetic basis of two rare disorders whose symptoms are apparently all caused by an altered immune system protein.
As reported by Hal M. Hoffman, M.D., and colleagues in today's online edition (the November print edition) of Nature Genetics, the protein, which they have named cryopyrin, is the likely culprit in two periodic fever syndromes: familial cold autoinflammatory syndrome (FCAS), in which affected people develop rashes and other symptoms when exposed to cold air, and Muckle-Wells syndrome (MWS), which causes deafness as well as periodic fevers.
Autoinflammatory conditions are those in which the body reacts as though it were being attacked by foreign organisms, despite the absence of such an attack.
"Although these conditions are rare, they cause a considerable amount of misery. People with FCAS, for example, develop rash and flu-like symptoms, such as chills, fever and achy joints, when exposed to cool air, such as in air-conditioned rooms," says Dr. Hoffman, a grantee of the National Institute of Allergy and Infectious Diseases (NIAID).
The identification of the gene underlying FCAS and MWS not only helps researchers understand the origin of these rare conditions, but may also give direction to the search for causes and mechanisms at work in more common conditions.
"As we begin to better understand cryopyrin, which evidently is a key regulatory protein, we are likely to learn more about such autoinflammatory diseases as Crohn's disease," says Marshall Plaut, M.D., chief of NIAID's Allergic Mechanisms Section.
Dr. Hoffman and his colleagues at the University of California, San Diego, analyzed the DNA of members of four families who have either FCAS or Muckle-Wells syndrome.
The researchers located four different mutations in the gene for cryopyrin. Each affected person studied had a mutation in this gene. In contrast, these mutations were not found in any unaffected family members or in random North American blood bank samples. "This provides strong evidence that these mutations cause FCAS and MWS," write the authors.
An analysis of the structure of cryopyrin revealed important clues to its possible role. For example, Dr. Hoffman notes, the protein contains a pyrin segment. Pyrin is an immune system protein thought to play a part in inflammation and cell death.
Normally, the body responds to infection with inflammation at the site of infection and often fever, explains Dr. Hoffman. In contrast, persons with FCAS, MWS, and other autoinflammatory disorders have hypersensitive immune systems that react with inflammation, even though their bodies are not under attack.
The researchers named the protein cryopyrin, which means icy fire, both because it has a structural similarity to pyrin and because its shape, and hence its function, may be changed by cold. The genetic mutations identified by the team lead to changes in cryopyrin.
However, the exact mechanism whereby cryopyrin influences inflammatory reactions throughout the body is still unknown, Dr. Hoffman notes.
Based on structural similarities between cryopyrin and proteins used by plants for defense against attackers, the scientists believe cryopyrin is part of the innate immune system-an evolutionarily ancient defense system-that is present in plants and other lower organisms.
When an immune system gene and its protein remain more or less unchanged through long periods of evolution, the implication is that the protein plays a central role in orchestrating immune defenses. If cryopyrin can be fitted into a broader picture of immune function as it developed over eons, more light may be shed on its role in normal and abnormal functioning of the human immune system as well.
NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.
HM Hoffman, JL Mueller, DH Broide, AA Wanderer and RD Kolodner. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nature Genetics. DOI: 10.1038/ng756. (published online Oct. 22, 2001).
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