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.
Abstract
Whole-exome sequencing reveals heterozygous RTEL1 mutations in familial pulmonary fibrosis with short telomeres http://ow.ly/LHvor
Footnotes
For editorial comments see Eur Respir J 2015; 46: 312–314 [DOI: 10.1183/13993003.00710-2015]
This article has supplementary material available from erj.ersjournals.com
Support statement: This work (exome sequencing) was supported by a grant “FPI-SPC” from Université Sorbonne Paris Cité and the Chancellerie des Universités de Paris (legs Poix). P. Revy and I. Callebaut are supported by institutional grants from INSERM, Ligue Nationale contre le Cancer (Equipe Labellisée La Ligue), INCa/Cancéropôle Ile de France, Institut Imagine and the European Research Council (PIDIMMUN grant number 249816). P. Revy is a scientist from the Centre National de la Recherche Scientifique (CNRS).
Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com
- Received March 12, 2015.
- Accepted April 11, 2015.
- Copyright ©ERS 2015