An international team of scientists, including several University
of Nebraska Medical Center researchers, has identified the gene involved
in X-linked lymphoproliferative syndrome (XLP). The disorder, also known
as Duncan’s disease, is marked by an extreme vulnerability to the Epstein-Barr
virus (EBV), a member of the herpes virus group that infects the majority
of individuals by adulthood.
The discovery, which is reported in the Oct. 1 edition of Nature
Genetics, is significant, as it will allow males at risk for XLP to be
diagnosed earlier, so that therapy can be given before it is too late.
In addition, it will permit the direct diagnosis of XLP in families with
a single affected male.
The team of scientists was headed locally by two professors in
the UNMC Department of Pathology and Microbiology — Janos Sumegi, M.D.,
Ph.D., and Thomas A. Seemayer, M.D. It included researchers from Boston
University School of Medicine as well as researchers from laboratories
in France, Germany, Great Britain and Italy.
XLP was first observed in 1969 by the late David T. Purtilo, M.D.,
former professor and chairman of pathology and microbiology at UNMC who
died in 1992. Males with XLP inherit a mutant gene in the X chromosome,
leaving them incapable of withstanding EBV. This immune deficiency passes
from unaffected women who are carriers to some of their male children.
By the time they are adults, more than 90 percent of Americans
are silently infected with EBV, a virus more common than chicken pox. However,
most infected people develop antibodies to fight the infection and have
little more than a sore throat or a slight fever.
Today, more than 88 unrelated families and 297 males are registered
in the XLP Registry at UNMC. Dr. Purtilo established the registry in 1978
to provide a central facility for coordinating research and serving as
a resource for diagnostic and therapeutic strategies. Dr. Seemayer is now
in charge of maintaining the XLP Registry.
Although XLP is a rare disorder occurring only as a genetic accident
with a frequency of one in every 1 million live births, it currently is
believed to be under diagnosed, Dr. Sumegi said.
After becoming infected with EBV, males born with XLP succumb
to either one or a combination of four diseases — mononucleosis, aplastic
anemia (bone marrow failure), lymphoma or hypogammaglobulinemia (the inability
to produce antibodies). About 75 percent of males with XLP die by age 10.
No one has lived past age 44.
Previous genetic, cytogenetic and physical mapping studies conducted
at UNMC and Boston University School of Medicine narrowed the search for
the XLP gene to a small region on the X chromosome, said Dr. Sumegi, who
spearheaded this work at UNMC. A variety of techniques, including DNA sequencing
and computer-based analysis, was used to isolate the gene, known as SH2D1A.
Presently, the only curative therapy for XLP is allogenic stem
cell transplantation. Age at the time of transplant appears to be critical,
Dr. Seemayer said. Of 13 boys transplanted, nine are alive and well without
recurrent disease, and all were under 15 years of age at the time of the
transplant. The four non-survivors were all over 15 years of age when they
were transplanted.
UNMC is the only public academic health science center in the
state. Through its commitment to research, education and patient care,
UNMC has established itself as one of the country’s leading centers for
cancer research and treatment and solid organ transplantation. More than
$34 million in research grants and contracts are awarded to UNMC scientists
annually. In addition, UNMC’s educational programs are responsible for
training more health professionals practicing in Nebraska than any other
institution.