Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis
Résumé
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 telomereassociated
genes implicated in FPF.