APHP Service de Génétique, Hôpital Bichat, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Paris, France These authors contributed equally to this work
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.
Eur Respir J. 2015 Aug;46(2):474-85. doi: 10.1183/09031936.00040115. Epub 2015 May 28.
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.
肺纤维化是一种具有进行性呼吸功能丧失的致命疾病。端粒维持缺陷导致端粒缩短是肺纤维化的一个原因，因为端粒酶成分基因 TERT（逆转录酶）和 TERC（RNA 成分）的突变在 15%的家族性肺纤维化（FPF）病例中被发现。然而，到目前为止，大约 85%的 FPF 仍然没有遗传特征。在这里，为了确定 FPF 的新遗传原因，我们对 35 个没有 TERT 和 TERC 突变的 FPF 家族的 47 名受影响的受试者进行了全外显子组测序和候选基因方法。我们在四个家族中发现了端粒伸长螺旋酶 1（RTEL1）的杂合突变。RTEL1 是一种 DNA 解旋酶，在 DNA 复制、基因组稳定性、DNA 修复和端粒维持中发挥作用。杂合 RTEL1 突变在 FPF 中呈常染色体显性遗传，结构分析预测这些突变会严重影响 RTEL1 的功能和/或稳定性。与这一结果一致的是，与年龄匹配的对照相比，携带 RTEL1 突变的患者的端粒较短。我们的研究结果提供了证据表明，杂合 RTEL1 突变是 FPF 的原因，从而扩展了 RTEL1 缺乏的临床谱。因此，RTEL1 增加了与端粒相关的基因在 FPF 中的数量。
