Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening

Bridget D Stuart; Jungmin Choi; Samir Zaidi; Chao Xing; Brody Holohan; Rui Chen; Mihwa Choi; Pooja Dharwadkar; Fernando Torres; Carlos E Girod; Jonathan Weissler; John Fitzgerald; Corey Kershaw; Julia Klesney-Tait; Yolanda Mageto; Jerry W Shay; Weizhen Ji; Kaya Bilguvar; Shrikant Mane; Richard P Lifton; Christine Kim Garcia

doi:10.1038/ng.3278

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Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening

Journal article

Peer reviewed

Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening

Bridget D Stuart, Jungmin Choi, Samir Zaidi, Chao Xing, Brody Holohan, Rui Chen, Mihwa Choi, Pooja Dharwadkar, Fernando Torres, Carlos E Girod, …

Nature genetics, Vol.47(5), pp.512-517

05/2015

DOI: 10.1038/ng.3278

PMCID: PMC4414891

PMID: 25848748

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https://www.ncbi.nlm.nih.gov/pmc/articles/4414891View

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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.

Amino Acid Sequence

Exoribonucleases - genetics

Genetic Predisposition to Disease

Idiopathic Pulmonary Fibrosis - genetics

Genetic Association Studies

Humans

Middle Aged

Cells, Cultured

Molecular Sequence Data

Male

Leukocytes - physiology

Case-Control Studies

Lod Score

Exome - genetics

Telomere Shortening

DNA Mutational Analysis

Pedigree

Aged, 80 and over

Idiopathic Pulmonary Fibrosis - pathology

Adult

Female

Aged

DNA Helicases - genetics

Telomere - genetics

Details

Title: Subtitle: Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening
Creators: Bridget D Stuart - 1] Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Jungmin Choi - 1] Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA. Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA
Samir Zaidi - 1] Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA. Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA
Chao Xing - Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Brody Holohan - Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Rui Chen - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Mihwa Choi - Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Pooja Dharwadkar - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Fernando Torres - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Carlos E Girod - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Jonathan Weissler - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
John Fitzgerald - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Corey Kershaw - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Julia Klesney-Tait - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Yolanda Mageto - Department of Internal Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
Jerry W Shay - Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Weizhen Ji - 1] Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA. Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA
Kaya Bilguvar - 1] Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA. Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut, USA
Shrikant Mane - 1] Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA. Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut, USA
Richard P Lifton - 1] Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA. Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA. Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut, USA. Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
Christine Kim Garcia - 1] Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Resource Type: Journal article
Publication Details: Nature genetics, Vol.47(5), pp.512-517
DOI: 10.1038/ng.3278
PMID: 25848748
PMCID: PMC4414891
NLM abbreviation: Nat Genet
ISSN: 1061-4036
eISSN: 1546-1718
Grant note: P30 ES005605 / NIEHS NIH HHS R01 HL093096 / NHLBI NIH HHS UL1TR001105 / NCATS NIH HHS Howard Hughes Medical Institute U54HG006504 / NHGRI NIH HHS R01HL093096 / NHLBI NIH HHS K12 HD068369 / NICHD NIH HHS U54 HG006504 / NHGRI NIH HHS K12HD068369 / NICHD NIH HHS UL1 TR001105 / NCATS NIH HHS P30 CA016359 / NCI NIH HHS T32 GM007205 / NIGMS NIH HHS P30 DK054759 / NIDDK NIH HHS
Language: English
Date published: 05/2015
Academic Unit: Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine
Record Identifier: 9984094531402771

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