• Caroline Kannengiesser, Raphael Borie, Christelle Ménard, Marion Réocreux, Patrick Nitschké, Steven Gazal, Hervé Mal, Camille Taillé, Jacques Cadranel, Hilario Nunes, Dominique Valeyre, Jean François Cordier, Isabelle Callebaut, Catherine Boileau, Vincent Cottin, Bernard Grandchamp, Patrick Revy, and Bruno Crestani.
• 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.
• Eur. Respir. J. 2015 Aug 1; 46 (2): 474-85.

AbstractPulmonary 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.Copyright ©ERS 2015.

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