Gene Mutations Linked To Hereditary Lung Disease

A progressive scarring of the lungs with no effective treatment, idiopathic pulmonary fibrosis (IPF) 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, Hopkins investigators screened DNA from blood samples of 73 people with inherited IPF and discovered that six of them (eight percent) had mutations in two genes that produce an enzyme which helps lengthen the fragile ends of chromosomes. Chromosome ends, or 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," says Mary Armanios, M.D., 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," says Armanios.

Patients with non-inherited IPF also may have short telomeres, so, says Armanios, "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 non-inherited IPF, investigators will need to study a larger group of these patients.

If studies reveal a solid link between the two, Armanios says that it may change the way IPF is treated.

"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 explains. "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 the Rudy W. Jacobson endowment.

Additional authors include Julian J.-L. Chen, Ph.D., and Mingyi Xie, B.S., from Arizona State University; Joy D. Cogan, Ph.D., Cheryl Markin, B.S., William E. Lawson, M.D., John A. Phillips III, M.D., and James E. Loyd, M.D., from Vanderbilt University; Irma Vulto, B.S., and Peter M. Lansdorp, M.D., Ph.D., from the University of British Columbia; and Jonathan K. Alder, B.A., Roxann G. Ingersoll, B.S., and Carol W. Greider, Ph.D., from Johns Hopkins

Citation: Armanios, MY, et al. Telomerase Mutations in Families with Idiopathic Pulmonary Fibrosis. NEJM 356; 13.