Scientists at Johns Hopkins have identified the
genetic culprits that trigger a hereditary form of a fatal
lung disease. The findings, published in the March 29
issue of The New England Journal of Medicine, may
provide new directions in diagnosis and treatment for
families that inherit genes for the disease, as well as
for those that develop noninherited forms of the
A progressive scarring of the lungs with no effective
treatment, idiopathic pulmonary fibrosis affects
approximately 50,000 Americans annually and, like some
cancers, often is fatal within three years. As many as 20
percent of IPF sufferers are thought to have inherited
genetic mistakes that predispose them to the disease, and,
until now, these gene flaws remained unknown.
To locate the genetic problem, Johns Hopkins
investigators screened DNA from blood samples of 73 people
with inherited IPF and discovered that six of them (8
percent) had mutations in two genes that produce an enzyme
that helps lengthen the fragile ends of chromosomes, or
telomeres. Telomeres contain repetitive bits of DNA code
that wear down each time a cell divides. The mutations
were spotted in two genes that regulate the enzyme
telomerase, which keeps telomere length extended just
beyond the borders of needed genes. With mutations in
telomerase, however, chromosome ends fray and wear down
far more quickly, which can trigger cell death.
The scientists' first hint that telomerase plays a
role in IPF came from studying the genetic traits of a
family with a rare premature aging disorder caused by
short telomeres. Many of the family members were suffering
from the disorder's second-leading cause of death —
pulmonary fibrosis. "We thought that perhaps there might
be a link between telomerase mutations and IPF," said Mary
Armanios, assistant professor of oncology at the Johns Hopkins
Kimmel Cancer Center.
In the current study, mutation carriers had telomeres
about one-third the length of those in family members with
no gene mistakes. Short telomeres also were found in seven
younger relatives who had gene mutations but not IPF.
Gene tests are currently not available for IPF, but
scientists are evaluating ways to assess risk of disease
by screening telomere length.
"If we follow the genetic threads of families that
inherit IPF, it may lead us to understand the genetic
properties causing more common forms of the disease,"
Patients with noninherited IPF also may have short
telomeres, Armanios said, so "there may be other causes
for short telomeres, such as older age and smoking, which
also happen to be the main risk factors for IPF."
To determine the link between short telomeres and
noninherited IPF, investigators will need to study a
larger group of these patients.
If studies reveal a solid link between the two,
Armanios said, the finding might change the way IPF is
"For many years, we've thought that IPF is caused by
an immune attack against the lungs, even though current
therapies aimed at dampening the immune system don't
work," she said. "If we're not so tied to immune
suppression therapies, we could eventually tailor drugs to
a different target."
Funding for the study was provided by the National
Institutes of Health, Richard C. Ross Johns Hopkins School
of Medicine Clinician Scientist Award, Maryland Cigarette
Restitution Fund Program at Johns Hopkins, Institute for
Cellular Engineering Pilot Program at Johns Hopkins,
Francis Family Foundation, Canadian Institute of Health
Research, Vanderbilt Discovery Grant and Rudy W. Jacobson
Additional authors are Julian J.-L. Chen and Mingyi
Xie, of Arizona State University; Joy D. Cogan, Cheryl
Markin, William E. Lawson, John A. Phillips III and James
E. Loyd, of Vanderbilt University; Irma Vulto and Peter M.
Lansdorp, of the University of British Columbia; and
Jonathan K. Alder, Roxann G. Ingersoll and Carol W.
Greider, of Johns Hopkins.