Title | Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Stuart, BD, Choi, J, Zaidi, S, Xing, C, Holohan, B, Chen, R, Choi, M, Dharwadkar, P, Torres, F, Girod, CE, Weissler, J, Fitzgerald, J, Kershaw, C, Klesney-Tait, J, Mageto, Y, Shay, JW, Ji, W, Bilguvar, K, Mane, S, Lifton, RP, Garcia, CKim |
Journal | Nat Genet |
Volume | 47 |
Issue | 5 |
Pagination | 512-7 |
Date Published | 2015 May |
ISSN | 1546-1718 |
Keywords | Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Case-Control Studies, Cells, Cultured, DNA Helicases, DNA Mutational Analysis, Exome, Exoribonucleases, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Idiopathic Pulmonary Fibrosis, Leukocytes, Lod Score, Male, Middle Aged, Molecular Sequence Data, Pedigree, Telomere, Telomere Shortening |
Abstract | Idiopathic pulmonary fibrosis (IPF) is an age-related disease featuring progressive lung scarring. To elucidate the molecular basis of IPF, we performed exome sequencing of familial kindreds with pulmonary fibrosis. Gene burden analysis comparing 78 European cases and 2,816 controls implicated PARN, an exoribonuclease with no previous connection to telomere biology or disease, with five new heterozygous damaging mutations in unrelated cases and none in controls (P = 1.3 × 10(-8)); mutations were shared by all affected relatives (odds in favor of linkage = 4,096:1). RTEL1, an established locus for dyskeratosis congenita, harbored significantly more new damaging and missense variants at conserved residues in cases than in controls (P = 1.6 × 10(-6)). PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic inheritance of short telomeres in family members. Together, these genes explain ~7% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction. |
DOI | 10.1038/ng.3278 |
Alternate Journal | Nat. Genet. |
PubMed ID | 25848748 |
PubMed Central ID | PMC4414891 |
Grant List | UL1 TR001105 / TR / NCATS NIH HHS / United States P30 ES005605 / ES / NIEHS NIH HHS / United States R01 HL093096 / HL / NHLBI NIH HHS / United States U54HG006504 / HG / NHGRI NIH HHS / United States U54 HG006504 / HG / NHGRI NIH HHS / United States R01HL093096 / HL / NHLBI NIH HHS / United States K12HD068369 / HD / NICHD NIH HHS / United States UL1TR001105 / TR / NCATS NIH HHS / United States T32 GM007205 / GM / NIGMS NIH HHS / United States / / Howard Hughes Medical Institute / United States P30 DK054759 / DK / NIDDK NIH HHS / United States P30 CA016359 / CA / NCI NIH HHS / United States K12 HD068369 / HD / NICHD NIH HHS / United States |