title: Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and 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.
authors.affiliation: 1] Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Bridget D
authors.initials: BD
authors.lastname: Stuart
authors.affiliation: 1] Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA. [2] Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Jungmin
authors.initials: J
authors.lastname: Choi
authors.affiliation: 1] Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA. [2] Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Zaidi
authors.affiliation: Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Xing
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Brody
authors.initials: B
authors.lastname: Holohan
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Mihwa
authors.initials: M
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Pooja
authors.initials: P
authors.lastname: Dharwadkar
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Torres
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Girod
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Weissler
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: John
authors.initials: J
authors.lastname: Fitzgerald
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Corey
authors.initials: C
authors.lastname: Kershaw
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Klesney-Tait
authors.affiliation: Department of Internal Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Mageto
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
authors.affiliation: 1] Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA. [2] Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Weizhen
authors.initials: W
authors.lastname: Ji
authors.affiliation: 1] Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA. [2] Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilguvar
authors.affiliation: 1] Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA. [2] Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Shrikant
authors.initials: S
authors.lastname: Mane
authors.affiliation: 1] Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA. [2] Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA. [3] Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut, USA. [4] Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: 1] Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Christine Kim
authors.initials: CK
authors.lastname: Garcia
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D002478:Cells, Cultured; D004265:DNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D005095:Exoribonucleases / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology; D007962:Leukocytes / Q000502:physiology; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D016615:Telomere / Q000235:genetics*; D059506:Telomere Shortening
chemical_list: D004265:DNA Helicases; D005095:Exoribonucleases; C532890:RTEL1 protein, human
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