The mutations affect an enzyme called telomerase, which is active in dividing cells such as stem cells and most cancerous cells. Different mutations in telomerase were found by screening patients and families with an inherited form of a disease called idiopathic pulmonary fibrosis, or IPF.
These findings, published online this week in Proceedings of the National Academy of Sciences, support evidence that normal lungs contain a population of cells that, like stem cells, divide to provide new cells in response to age or injury to keep the organ functional. The researchers found that deficiency of telomerase in the lungs may interfere with this self-repair mechanism, leading to IPF.
Because of what is known about telomerase, some cases of IPF can be considered the result of accelerated aging of the lung, said Dr. Christine Garcia, senior author of the study and assistant professor in the EugeneMcDermottCenter for Human Growth and Development and of internal medicine.
About 200,000 people in the United States have IPF, and about 50,000 new cases are diagnosed each year, according to the Pulmonary Fibrosis Foundation. The disease typically strikes people in their 50s or above, causing severe scarring of the lungs, with death usually occurring about three years after diagnosis.
There is no cure for IPF except lung transplantation. The cause might be a combination of genetic susceptibility and environmental influences such as smoking, Dr. Garcia said.
About one in 50 IPF patients, or approximately 2 percent, have an inherited form of the disease, Dr. Garcia said, and it's this genetic link that she and her colleagues focused on. We don't have a handle yet on all the genes that cause the majority of the cases, but this is a start, she said.
Telomerase is an enzyme that controls the lengths of DNA at the ends of chromosomes, called telomeres. In normal cells, where telomerase is inactive, telomeres shorten each time the cell divides. When they reach a certain length, the cell stops dividing. In stem cells and in most cancerous cells, however, telomerase is active, and the telomeres don't shorten during cell division, allowing the cells to remain effectively immortal.
The UT Southwestern researchers studied members of 46 families with two or more cases of lung scarring, and used two of the largest families to conduct a genetic hunt for the culprit gene.
This led to a gene called TERT, which codes for one portion of the telomerase enzyme. They found mutations in TERT in the two large families as well as in four other families. Many of the people with TERT mutations had symptoms of IPF, but some did not, which suggests environmental factors may contribute to the deadly lung disease.
The researchers also found one mutation in a gene called TERC, which codes for a second portion of telomerase.
All people in the study who carried any mutations in TERT or TERC had a deficiency in telomerase that led to shortened telomeres, even those who did not have evidence of lung scarring.
The researchers also found that people with the mutations often had other diseases, such as anemia and osteoporosis, suggesting that these mutations affect telomerase function in not only the lungs, but also in other organ systems.
By screening 44 patients with sporadic IPF, the researchers found one additional mutation in TERT , supporting the conclusion that TERT mutations might be involved in some cases of the more common noninherited form of the disease.
Other UT Southwestern researchers involved in the study were Kalliopi Tsakiri, a graduate student from the University of Crete; Jennifer Cronkhite, senior research associate in the McDermott Center; medical student Phillip Kuan; Dr. Chao Xing, assistant professor of clinical sciences; Dr. Jonathan Weissler, professor of internal medicine and chief of pulmonary/critical care medicine; Dr. Randall Rosenblatt, professor of internal medicine; and Dr. Jerry Shay, professor of cell biology.
Dr. Ganesh Raghu of the University of Washington Medical Center also participated.
The work was supported by the National Institutes of Health, a NASA Specialized Center of Research, the JamesMllinsCenter for Biomedical Research, the Will Rogers Institute and the UT Southwestern President's Research Council.
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