Natural history of pulmonary fibrosis in two subjects with the same telomerase mutation.
Previous studies have identified subclinical lung disease in family members of probands with familial pulmonary fibrosis, but the natural history of preclinical pulmonary fibrosis is uncertain. The purpose of this study was to determine whether individuals with preclinical lung disease will develop pulmonary fibrosis. After a 27-year interval, two subjects with manifestations of preclinical familial pulmonary fibrosis, including asymptomatic alveolar inflammation and alveolar macrophage activation, were reevaluated for lung disease. CT scans of the chest, pulmonary function tests, and BAL were performed, and genomic DNA was analyzed for mutations in candidate genes associated with familial pulmonary fibrosis. One subject developed symptomatic familial pulmonary fibrosis and was treated with oxygen; her sister remained asymptomatic but had findings of pulmonary fibrosis on high-resolution CT scan of the chest. High concentrations of lymphocytes were found in BAL fluid from both subjects. Genetic sequencing and analyses identified a novel heterozygous mutation in telomerase reverse transcriptase (TERT, R1084P), resulting in telomerase dysfunction and short telomeres in both subjects. In familial pulmonary fibrosis, asymptomatic preclinical alveolar inflammation associated with mutation in TERT and telomerase insufficiency can progress to fibrotic lung disease over 2 to 3 decades.


BACKGROUND
ClinicalTrials.gov; No.: NCT00071045; URL: www.clinicaltrials.gov.
Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, MD.
Souheil
S
El-Chemaly
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
Shira G
SG
Ziegler
Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD.
Rodrigo T
RT
Calado
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
Kirkland A
KA
Wilson
Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD.
Hai Ping
HP
Wu
Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD.
Mary
M
Haughey
Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD.
Nathan R
NR
Peterson
Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD.
Neal S
NS
Young
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
William A
WA
Gahl
Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, MD.
Joel
J
Moss
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD. Electronic address: gochuicb@mail.nih.gov.
Bernadette R
BR
Gochuico
D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005500:Follow-Up Studies; D006801:Humans; D008137:Longitudinal Studies; D008875:Middle Aged; D009154:Mutation; D011658:Pulmonary Fibrosis / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*
D019098:Telomerase