Abstract

Background: Mutations in the human gene encoding the protein component of telomerase (TERT) are the most common genetic defect in patients with familial idiopathic pulmonary fibrosis (IPF). The subclinical phenotypes of asymptomatic members of these families have not been evaluated with respect to TERT mutation status or telomere length. Methods: We measured a variety of pulmonary, blood, skin, and bone parameters for 20 subjects with heterozygous TERT mutations (carriers) and 20 family members who had not inherited a TERT mutation (noncarriers) to identify the spectrum of phenotypes associated with mutations in this gene. The two groups were matched for sex, age, and cigarette smoking. Three TERT mutation carriers had IPF (IPF carriers). The rest of the carriers were apparently healthy (asymptomatic carriers) and were compared with the noncarriers. Results: Asymptomatic carriers exhibited significantly lower diffusing capacity of lung for carbon monoxide (DLCO), impaired recruitment of DLCO with exercise, radiographic signs of lung fibrosis, and increased fractional lung tissue volume quantified by high-resolution chest CT scan than noncarriers. RBC and platelet counts were significantly lower, and the mean corpuscular volume and mean corpuscular hemoglobin concentration were significantly higher in carriers than in noncarriers. Carriers reported significantly earlier graying of hair than noncarriers. TERT mutation status is more accurately predicted by short telomere lengths than any of these measured phenotypes. Conclusions: TERT mutation carriers exhibit early preclinical signs of lung fibrosis, bone marrow dysfunction, and premature graying. These clinical features and short telomere lengths characterize patients with germline TERT mutations.

Original languageEnglish (US)
Pages (from-to)753-763
Number of pages11
JournalChest
Volume140
Issue number3
DOIs
StatePublished - Sep 1 2011

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Telomerase
Lung Diseases
Mutation
Idiopathic Pulmonary Fibrosis
Telomere
Lung
Erythrocyte Indices
Phenotype
Lung Volume Measurements
Primary Myelofibrosis
Germ-Line Mutation
Carbon Monoxide
Platelet Count
Hair
Fibrosis
Research Design
Thorax
Smoking
Exercise
Bone and Bones

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

@article{853fdba22e2f45ef97ca54e5787f4e13,
title = "Subclinical lung disease, macrocytosis, and premature graying in kindreds with telomerase (TERT) mutations",
abstract = "Background: Mutations in the human gene encoding the protein component of telomerase (TERT) are the most common genetic defect in patients with familial idiopathic pulmonary fibrosis (IPF). The subclinical phenotypes of asymptomatic members of these families have not been evaluated with respect to TERT mutation status or telomere length. Methods: We measured a variety of pulmonary, blood, skin, and bone parameters for 20 subjects with heterozygous TERT mutations (carriers) and 20 family members who had not inherited a TERT mutation (noncarriers) to identify the spectrum of phenotypes associated with mutations in this gene. The two groups were matched for sex, age, and cigarette smoking. Three TERT mutation carriers had IPF (IPF carriers). The rest of the carriers were apparently healthy (asymptomatic carriers) and were compared with the noncarriers. Results: Asymptomatic carriers exhibited significantly lower diffusing capacity of lung for carbon monoxide (DLCO), impaired recruitment of DLCO with exercise, radiographic signs of lung fibrosis, and increased fractional lung tissue volume quantified by high-resolution chest CT scan than noncarriers. RBC and platelet counts were significantly lower, and the mean corpuscular volume and mean corpuscular hemoglobin concentration were significantly higher in carriers than in noncarriers. Carriers reported significantly earlier graying of hair than noncarriers. TERT mutation status is more accurately predicted by short telomere lengths than any of these measured phenotypes. Conclusions: TERT mutation carriers exhibit early preclinical signs of lung fibrosis, bone marrow dysfunction, and premature graying. These clinical features and short telomere lengths characterize patients with germline TERT mutations.",
author = "{Diaz De Leon}, Alberto and Cronkhite, {Jennifer T.} and Cuneyt Yilmaz and Cecelia Brewington and Richard Wang and Chao Xing and Hsia, {Connie C W} and Garcia, {Christine Kim}",
year = "2011",
month = "9",
day = "1",
doi = "10.1378/chest.10-2865",
language = "English (US)",
volume = "140",
pages = "753--763",
journal = "Chest",
issn = "0012-3692",
publisher = "American College of Chest Physicians",
number = "3",

}

TY - JOUR

T1 - Subclinical lung disease, macrocytosis, and premature graying in kindreds with telomerase (TERT) mutations

AU - Diaz De Leon, Alberto

AU - Cronkhite, Jennifer T.

AU - Yilmaz, Cuneyt

AU - Brewington, Cecelia

AU - Wang, Richard

AU - Xing, Chao

AU - Hsia, Connie C W

AU - Garcia, Christine Kim

PY - 2011/9/1

Y1 - 2011/9/1

N2 - Background: Mutations in the human gene encoding the protein component of telomerase (TERT) are the most common genetic defect in patients with familial idiopathic pulmonary fibrosis (IPF). The subclinical phenotypes of asymptomatic members of these families have not been evaluated with respect to TERT mutation status or telomere length. Methods: We measured a variety of pulmonary, blood, skin, and bone parameters for 20 subjects with heterozygous TERT mutations (carriers) and 20 family members who had not inherited a TERT mutation (noncarriers) to identify the spectrum of phenotypes associated with mutations in this gene. The two groups were matched for sex, age, and cigarette smoking. Three TERT mutation carriers had IPF (IPF carriers). The rest of the carriers were apparently healthy (asymptomatic carriers) and were compared with the noncarriers. Results: Asymptomatic carriers exhibited significantly lower diffusing capacity of lung for carbon monoxide (DLCO), impaired recruitment of DLCO with exercise, radiographic signs of lung fibrosis, and increased fractional lung tissue volume quantified by high-resolution chest CT scan than noncarriers. RBC and platelet counts were significantly lower, and the mean corpuscular volume and mean corpuscular hemoglobin concentration were significantly higher in carriers than in noncarriers. Carriers reported significantly earlier graying of hair than noncarriers. TERT mutation status is more accurately predicted by short telomere lengths than any of these measured phenotypes. Conclusions: TERT mutation carriers exhibit early preclinical signs of lung fibrosis, bone marrow dysfunction, and premature graying. These clinical features and short telomere lengths characterize patients with germline TERT mutations.

AB - Background: Mutations in the human gene encoding the protein component of telomerase (TERT) are the most common genetic defect in patients with familial idiopathic pulmonary fibrosis (IPF). The subclinical phenotypes of asymptomatic members of these families have not been evaluated with respect to TERT mutation status or telomere length. Methods: We measured a variety of pulmonary, blood, skin, and bone parameters for 20 subjects with heterozygous TERT mutations (carriers) and 20 family members who had not inherited a TERT mutation (noncarriers) to identify the spectrum of phenotypes associated with mutations in this gene. The two groups were matched for sex, age, and cigarette smoking. Three TERT mutation carriers had IPF (IPF carriers). The rest of the carriers were apparently healthy (asymptomatic carriers) and were compared with the noncarriers. Results: Asymptomatic carriers exhibited significantly lower diffusing capacity of lung for carbon monoxide (DLCO), impaired recruitment of DLCO with exercise, radiographic signs of lung fibrosis, and increased fractional lung tissue volume quantified by high-resolution chest CT scan than noncarriers. RBC and platelet counts were significantly lower, and the mean corpuscular volume and mean corpuscular hemoglobin concentration were significantly higher in carriers than in noncarriers. Carriers reported significantly earlier graying of hair than noncarriers. TERT mutation status is more accurately predicted by short telomere lengths than any of these measured phenotypes. Conclusions: TERT mutation carriers exhibit early preclinical signs of lung fibrosis, bone marrow dysfunction, and premature graying. These clinical features and short telomere lengths characterize patients with germline TERT mutations.

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U2 - 10.1378/chest.10-2865

DO - 10.1378/chest.10-2865

M3 - Article

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JO - Chest

JF - Chest

SN - 0012-3692

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