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Eur Respir J. 2015 Aug;46(2):474-85. doi: 10.1183/09031936.00040115. Epub 2015 May 28.

Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis.

Author information

1
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.
2
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.
3
APHP Service de Génétique, Hôpital Bichat, Paris, France.
4
Université Paris Diderot, Sorbonne Paris Cité, Paris, France Imagine Institute, Paris, France.
5
Université Paris Diderot, Sorbonne Paris Cité, Paris, France Inserm, IAME, UMR 1137, Paris, France Plateforme de Génétique constitutionnelle-Nord (PfGC-Nord), Paris, France.
6
APHP Service de Pneumologie B, Hôpital Bichat, Paris, France.
7
APHP, Hôpital Bichat, Service de Pneumologie A, DHU FIRE Centre de compétence des maladies pulmonaires rares, Paris, France.
8
APHP, Service de Pneumologie, Centre de compétence des maladies pulmonaires rares, Hôpital Tenon, Paris, France Université paris 6, Paris, France.
9
APHP, Service de Pneumologie, Hôpital Avicenne, Centre de Compétence des Maladies Pulmonaires Rares, Bobigny, France Université Paris 13, Paris, France.
10
Université Claude Bernard Lyon 1, Lyon, France Service de Pneumologie, Centre national de référence des maladies pulmonaires rares, Hôpital Louis Pradel, Lyon, France.
11
IMPMC, Sorbonne Universités - UPMC Univ Paris 06, UMR CNRS 7590, Museum National d'Histoire Naturelle, IRD UMR 206, IUC, Paris, France.
12
APHP Service de Génétique, Hôpital Bichat, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
13
Imagine Institute, Paris, France Laboratory of Genome Dynamics in the Immune System, INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France.
14
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.

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.

PMID:
26022962
DOI:
10.1183/09031936.00040115
[Indexed for MEDLINE]
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