An international team of
researchers has discovered genetic mutations underlying a newly recognized
group of inherited inflammatory disorders. These illnesses, one of which was
first described in a family of Irish and Scottish descent, are characterized
by dramatic, sometimes month-long episodes of high fever, severe pain in the
abdomen, chest, or joints, skin rash, and inflammation in or around the eyes.
Some patients also develop a potentially fatal complication called amyloidosis,
a disease in which there is deposition of a blood protein in vital organs.
Results of the study are
published as the lead article in the April 2 issue of the journal Cell.
Patients from seven different families with symptoms of these disorders were
found to have mutations in a cell surface receptor for an inflammatory protein
called tumor necrosis factor (TNF). Normally this receptor plays a role in the
body's defenses against infectious and foreign agents. The Cell article
explains that mutations in the receptor are responsible for a predisposition
to severe inflammation triggered by daily life events such as emotional
stress, minor trauma, or for seemingly no apparent reason. This discovery
marks the first time that TNF receptor mutations have been tied to an
"These results are very
important in helping us further understand the role of the TNF pathway in
disease, and may lead to additional treatments, targeted at the cellular
level, for many immune-related and inflammatory disorders," said Dr.
Stephen I. Katz, Director of the National Institute of Arthritis and
Musculoskeletal and Skin Diseases (NIAMS) in Bethesda, Maryland.
The senior author of the
report is Dr. Daniel Kastner, a physician-scientist in the Intramural Research
Program of NIAMS. Almost two years ago Kastner had successfully led an
international consortium in the cloning of the gene for familial Mediterranean
fever (FMF), another hereditary disorder of fever and inflammation that is
common among people of Jewish, Arab, Armenian, and Turkish ancestry.
After the FMF gene was
identified, it became clear that some families with periodic fevers do not
have these FMF mutations. Several of these families have been noted to show a
dominant mode of inheritance (FMF is recessive), and are not of Mediterranean
ancestry. The symptoms most frequently reported by the affected individuals
include fever lasting a week or more, accompanied by red and swollen eyes,
migratory skin rashes, muscle tenderness, joint pain, and sometimes abdominal
or chest pain. An unusually high incidence of inguinal hernia has been noted
in affected men. Some patients also develop amyloidosis, which can be fatal.
One of the
best-characterized families is of Irish and Scottish ancestry, and was first
described by a research team at the Queen's Medical Centre in Nottingham,
England. To contrast this condition from FMF and emphasize the Irish ancestry,
they named it familial Hibernian fever (FHF). However, families with similar
complaints have now been described in several ethnic groups. Initially, it was
not clear whether all of these families had mutations in the same gene or in
several related genes.
A key advance came about one
year ago when two research teams independently identified a region of
chromosome 12 associated with susceptibility to this form of periodic fever.
One research team was headed by Dr. Michael McDermott, of the Royal London
School of Medicine, formerly a postdoctoral fellow in Kastner's lab. The
second team is in Adelaide, Australia, and subsequently a third team of
researchers in Helsinki extended these results to a large Finnish family.
At a meeting hosted by Dr.
Kastner last year, these research teams and scientists from Cork, Ireland,
agreed to collaborate to determine which particular gene on chromosome 12
causes periodic fevers. The target region contained as many as 500 different
genes, and the group prepared for a lengthy search. Among the possibilities
was the gene for the TNF receptor 1 (TNFR1). This receptor is found embedded
in the cell membranes of most cells in the body, where it acts as the
transponder for TNF by receiving and transmitting signals that trigger an
inflammatory response. The inflammatory signal can be turned off by removal of
the TNF receptor from the surface of the cell, a process called
"shedding." The portion that is released can suppress the
inflammatory response by absorbing TNF before it reaches cells to transmit its
signal. Even before TNFR1 was known to be located in the target region of
chromosome 12, the Nottingham group had found low levels of soluble TNFR1 in
the blood of Hibernian fever patients.
McDermott worked with Dr.
Ivona Aksentijevich in the Kastner laboratory to screen the TNFR1 gene for
sequence differences between patient and normal groups. On Thanksgiving Day,
1998, they found the first unmistakable changes in the DNA sequence.
Ultimately, the consortium found six disease-associated mutations. Because
these mutations were found in families of several different ethnic
backgrounds, the authors have proposed the more neutral acronym TRAPS (TNF
Receptor-Associated Periodic Syndrome) to include all of the families.
Drs. Jérôme Galon and John
O'Shea, colleagues of Kastner's, have studied how these mutations cause
disease. In a Louisiana family with TRAPS who were patients at NIAMS, these
researchers found that the TNFR1 mutation prevented normal shedding of
receptor after cellular activation. This could result in prolonged signaling
by TNF at the cell surface, and diminished soluble TNFR1 in the blood to
absorb TNF and block signaling.
Based on this analysis,
Kastner and his colleagues believe that a synthetic form of TNF receptor might
help to suppress the inflammation these patients experience. Fortuitously, a
drug recently approved for the treatment of rheumatoid arthritis is in fact
the shed form of a related TNF receptor. Researchers will now determine the
potential usefulness of this drug in the treatment of TRAPS. Currently, many
patients are treated with high doses of steriods, which can have serious
side-effects and are not completely effective.
The photo on the cover of
the journal shows massive deposits of amyloid in kidney of a patient who died
of TRAPS. Kastner expressed hope that the discovery of TNFR1 mutations will
help this patient's sister, niece, and 8 year-old daughter to avoid a similar
fate. "It is absolutely incredible to live in a time when we have the
tools to find the exact molecular cause of a baffling disease, and then to be
able to do something about it," observes Kastner. "It's such a
privilege to have this opportunity."
The National Institute of
Arthritis and Musculoskeletal and Skin Diseases leads the Federal biomedical
research effort on rheumatic diseases by conducting and supporting research
projects, research training, clinical trials, and epidemiologic studies, and
through dissemination of health information and research results.
To reach Dr. Dan Kastner for
Office of Communications and Public Liaison
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Reference: McDermott MF,
Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, Mansfield E,
Gadina M, Karenko L, Pettersson T, McCarthy J, Frucht D, Aringer M, Torosyan
Y, Teppo A-M, Wilson M, Karaarslan HM, Wan Y, Todd I, Wood G, Schlimgen R,
Kumarajeewa TR, Cooper SM, Vella JP, Amos CI, Mulley J, Quane KA, Molloy MG,
Ranki A, Powell RJ, Hitman GA, O'Shea JJ, Kastner DL. Germline mutations in
the extracellular domains of the 55 kDa TNF Receptor, TNFR1, define a family
of dominantly inherited autoinflammatory syndromes. Cell 97: 133-144, 1999.
Note: first authors Ivona
Aksentijevich and Jérôme Galon of the NIAMS, and Michael McDermott of St.
Bartholomew's and the Royal London Hospital School of Medicine and Dentistry
contributed equally to this work. The senior author is Dr. Daniel L. Kastner.
Portions of this work were
supported by the Research Advisory Committee of the Special Trustees, the
Royal London Hospitals NHS Trust; the Jones Charitable Trust, Nottingham, UK;
the National Health and Medical Research Council of Australia; and the Medical
Research Funcs of Tampere and Helsinki University Hospitals, Tampere and