Mutations in two genes cause a fatal lung scarring disease known as familial pulmonary fibrosis and can cause excessive shortening of the ends of chromosomes, known as telomeres. Telomeres are repetitive sequences of DNA that protect the ends of chromosomes from deteriorating. Think of them like the plastic ends of shoelaces, which protect shoelaces from fraying. 

Together, these genes PARN and RTEL1 explain about 7 percent of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction. According to the study,  about 50,000 people in the United States annually develop idiopathic pulmonary fibrosis, a progressive disease that principally affects the elderly. Approximately one in 20 people have a close relative with the disease, in which case they are considered to have familial pulmonary fibrosis. Without a lung transplant, pulmonary fibrosis patients typically die within three years after diagnosis. 

Dr. Christine Kim Garcia, Associate Professor of Internal Medicine and with the Eugene McDermott Center for Human Growth and Development. Credit: UT Southwestern Medical Center

"Although RTEL1 had been previously linked to telomere biology, our finding that PARN was involved in telomere regulation and human disease was completely unexpected," said senior author Dr. Christine Kim Garcia, Associate Professor of Internal Medicine and with the Eugene McDermott Center for Human Growth and Development at UT Southwestern Medical Center. 

The research team identified 99 families that had the inherited form of the disease, but did not have mutations in one of the previously identified genes. Using a technique known as exome sequencing, the researchers identified mutations in PARN and RTEL1 in 12 percent of these families.

"There were statistically more mutations found in these two genes than you would expect by chance," Dr. Garcia said.

The researchers used quantitative PCR (real-time polymerase chain reaction) to measure telomere lengths in these patients. 

"We found that the mean, age-adjusted telomere length of all rare variant carriers was significantly shorter than normal controls," said the study's first author, Dr. Bridget Stuart, Assistant Professor of Pediatrics and with the Eugene McDermott Center for Human Growth and Development. "This finding implicates both genes in telomere maintenance as well as development of pulmonary fibrosis." 

Published in Nature Genetics. Other UT Southwest researchers who contributed to the study are Dr. Chao Xing, Associate Professor of Clinical Sciences and with the Eugene McDermott Center for Human Growth and Development; Brody Holohan, student researcher; Mihwa Choi, Senior Research Scientist; Dr. Pooja Dharwadkar, resident; Dr. Fernando Torres, Associate Professor of Internal Medicine and Medical Director of the Lung Transplant Program; Dr. Carlos E. Girod, Professor of Internal Medicine who holds the Ron Anderson, M.D. Professorship in Clinical Care and Education at Parkland Memorial Hospital; Dr. Jonathan Weissler, Vice Chair of Clinical Affairs for UT Southwestern University Hospitals, Professor of Internal Medicine and Immunology and holder of the James M. Collins Professorship in Biomedical Research; Dr. John Fitzgerald, Professor Internal Medicine and holder of the Elaine Dewey Sammons Chair in Pulmonary Research, in Honor of John E. Fitzgerald, M.D.; Dr. Corey Kershaw, Associate Professor of Internal Medicine and Medical Director of the Medical Intensive Care Unit and Respiratory Therapy at William P. Clements Jr. University Hospital; and Dr. Jerry Shay, Professor of Cell Biology who holds the Southland Financial Corporation Distinguished Chair in Geriatrics. Former UT Southwestern researchers Dr. Julia Klesney-Tait and Dr. Yolanda Mageto, and researchers from the Yale Center for Genome Analysis also contributed.

The study was supported by the National Institutes of Health's National Center for Advancing Translational Sciences and the Howard Hughes Medical Institute.