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
N1 - Funding Information:
Funding/Support: This work was supported by the National Institutes of Health [ grants HL093096 (C. K. G.), HL097010 [(C. Y.) and DK063242 (C. C. W. H.) ], the Doris Duke Charitable Foundation (A. D. and C. K. G.), and the American Heart Association (C. K. G.).
Funding Information:
Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Wang has received grant money from the University of Texas Southwestern Medical Center at Dallas in the form of salary support provided to the Department of Dermatology. He also has received support from Galderma Laboratories, LP, in the form of unrestricted research grants for pilot projects. Dr Garcia has received other grant monies. Drs Diaz de Leon, Cronkhite, Yilmaz, Brewington, Xing, and Hsia have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
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
C2 - 21349926
AN - SCOPUS:80052666657
SN - 0012-3692
VL - 140
SP - 753
EP - 763
JO - CHEST
JF - CHEST
IS - 3
ER -