title: Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis.
abstract: Pulmonary fibrosis is a fatal disease with progressive loss of respiratory function. Defective telomere maintenance leading to telomere shortening is a cause of pulmonary fibrosis, as mutations in the telomerase component genes TERT (reverse transcriptase) and TERC (RNA component) are found in 15% of familial pulmonary fibrosis (FPF) cases. However, so far, about 85% of FPF remain genetically uncharacterised.Here, in order to identify new genetic causes of FPF, we performed whole-exome sequencing, with a candidate-gene approach, of 47 affected subjects from 35 families with FPF without TERT and TERC mutations.We identified heterozygous mutations in regulator of telomere elongation helicase 1 (RTEL1) in four families. RTEL1 is a DNA helicase with roles in DNA replication, genome stability, DNA repair and telomere maintenance. The heterozygous RTEL1 mutations segregated as an autosomal dominant trait in FPF, and were predicted by structural analyses to severely affect the function and/or stability of RTEL1. In agreement with this, RTEL1-mutated patients exhibited short telomeres in comparison with age-matched controls.Our results provide evidence that heterozygous RTEL1 mutations are responsible for FPF and, thereby, extend the clinical spectrum of RTEL1 deficiency. Thus, RTEL1 enlarges the number of telomere-associated genes implicated in FPF.
authors.affiliation: APHP Service de Génétique, Hôpital Bichat, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Paris, France These authors contributed equally to this work caroline.kannengiesser@bch.aphp.fr.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kannengiesser
authors.affiliation: APHP, Hôpital Bichat, Service de Pneumologie A, DHU FIRE Centre de compétence des maladies pulmonaires rares, Paris, France These authors contributed equally to this work.
authors.forename: Raphael
authors.initials: R
authors.lastname: Borie
authors.affiliation: APHP Service de Génétique, Hôpital Bichat, Paris, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Ménard
authors.affiliation: APHP Service de Génétique, Hôpital Bichat, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Réocreux
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Paris, France Imagine Institute, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschké
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Paris, France Inserm, IAME, UMR 1137, Paris, France Plateforme de Génétique constitutionnelle-Nord (PfGC-Nord), Paris, France.
authors.forename: Steven
authors.initials: S
authors.lastname: Gazal
authors.affiliation: APHP Service de Pneumologie B, Hôpital Bichat, Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Mal
authors.affiliation: APHP, Hôpital Bichat, Service de Pneumologie A, DHU FIRE Centre de compétence des maladies pulmonaires rares, Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Taillé
authors.affiliation: APHP, Service de Pneumologie, Centre de compétence des maladies pulmonaires rares, Hôpital Tenon, Paris, France Université paris 6, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Cadranel
authors.affiliation: APHP, Service de Pneumologie, Hôpital Avicenne, Centre de Compétence des Maladies Pulmonaires Rares, Bobigny, France Université Paris 13, Paris, France.
authors.forename: Hilario
authors.initials: H
authors.lastname: Nunes
authors.affiliation: APHP, Service de Pneumologie, Hôpital Avicenne, Centre de Compétence des Maladies Pulmonaires Rares, Bobigny, France Université Paris 13, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Valeyre
authors.affiliation: Université Claude Bernard Lyon 1, Lyon, France Service de Pneumologie, Centre national de référence des maladies pulmonaires rares, Hôpital Louis Pradel, Lyon, France.
authors.forename: Jean François
authors.initials: JF
authors.lastname: Cordier
authors.affiliation: IMPMC, Sorbonne Universités - UPMC Univ Paris 06, UMR CNRS 7590, Museum National d'Histoire Naturelle, IRD UMR 206, IUC, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Callebaut
authors.affiliation: APHP Service de Génétique, Hôpital Bichat, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.affiliation: Université Claude Bernard Lyon 1, Lyon, France Service de Pneumologie, Centre national de référence des maladies pulmonaires rares, Hôpital Louis Pradel, Lyon, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cottin
authors.affiliation: APHP Service de Génétique, Hôpital Bichat, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Grandchamp
authors.affiliation: Imagine Institute, Paris, France Laboratory of Genome Dynamics in the Immune System, INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Revy
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Paris, France APHP, Hôpital Bichat, Service de Pneumologie A, DHU FIRE Centre de compétence des maladies pulmonaires rares, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Crestani
mesh_terms: D000328:Adult; D004265:DNA Helicases / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019098:Telomerase / Q000235:genetics; D059506:Telomere Shortening
chemical_list: D019098:Telomerase; C532890:RTEL1 protein, human; D004265:DNA Helicases