Telomerase mutations in families with idiopathic pulmonary fibrosis.
BACKGROUND
Idiopathic pulmonary fibrosis is progressive and often fatal; causes of familial clustering of the disease are unknown. Germ-line mutations in the genes hTERT and hTR, encoding telomerase reverse transcriptase and telomerase RNA, respectively, cause autosomal dominant dyskeratosis congenita, a rare hereditary disorder associated with premature death from aplastic anemia and pulmonary fibrosis.


METHODS
To test the hypothesis that familial idiopathic pulmonary fibrosis may be caused by short telomeres, we screened 73 probands from the Vanderbilt Familial Pulmonary Fibrosis Registry for mutations in hTERT and hTR.


RESULTS
Six probands (8%) had heterozygous mutations in hTERT or hTR; mutant telomerase resulted in short telomeres. Asymptomatic subjects with mutant telomerase also had short telomeres, suggesting that they may be at risk for the disease. We did not identify any of the classic features of dyskeratosis congenita in five of the six families.


CONCLUSIONS
Mutations in the genes encoding telomerase components can appear as familial idiopathic pulmonary fibrosis. Our findings support the idea that pathways leading to telomere shortening are involved in the pathogenesis of this disease.
Armanios
Mary Y
MY
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. marmani1@jhmi.edu
Chen
Julian J-L
JJ
Cogan
Joy D
JD
Alder
Jonathan K
JK
Ingersoll
Roxann G
RG
Markin
Cheryl
C
Lawson
William E
WE
Xie
Mingyi
M
Vulto
Irma
I
Phillips
John A
JA
Lansdorp
Peter M
PM
Greider
Carol W
CW
Loyd
James E
JE
D005260:Female; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D011658:Pulmonary Fibrosis / Q000000981:diagnostic imaging / Q000235:genetics*; D012313:RNA / Q000235:genetics*; D011859:Radiography; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000201:enzymology / Q000235:genetics / Q000473:pathology*
C422952:telomerase RNA; D012313:RNA; D019098:Telomerase