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
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.
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.
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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.
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