Genetic analyses of aplastic anemia and idiopathic pulmonary fibrosis patients with short telomeres, possible implication of DNA-repair genes

Abstract

Background Telomeres are nucleoprotein structures present at the terminal region of the chromosomes. Mutations in genes coding for proteins involved in telomere maintenance are causative of a number of disorders known as telomeropathies. The genetic origin of these diseases is heterogeneous and has not been determined for a significant proportion of patients. Methods This article describes the genetic characterization of a cohort of patients. Telomere length was determined by Southern blot and quantitative PCR. Nucleotide variants were analyzed either by high-resolution melting analysis and Sanger sequencing of selected exons or by massive sequencing of a panel of genes. Results Forty-seven patients with telomere length below the 10% of normal population, affected with three telomeropathies: dyskeratosis congenita (4), aplastic anemia (22) or pulmonary fibrosis (21) were analyzed. Eighteen of these patients presented known pathogenic or novel possibly pathogenic variants in the telomere-related genes TERT , TERC , RTEL1 , CTC1 and ACD . In addition, the analyses of a panel of 188 genes related to haematological disorders indicated that a relevant proportion of the patients (up to 35%) presented rare variants in genes related to DNA repair or in genes coding for proteins involved in the resolution of complex DNA structures, that participate in telomere replication. Mutations in some of these genes are causative of several syndromes previously associated to telomere shortening. Conclusion Novel variants in telomere, DNA repair and replication genes are described that might indicate the contribution of variants in these genes to the development of telomeropathies. Patients carrying variants in telomere-related genes presented worse evolution after diagnosis than the rest of patients analyzed. Electronic supplementary material The online version of this article (10.1186/s13023-019-1046-0) contains supplementary material, which is available to authorized users.

Integrative Analyses Reveal Novel Disease-associated Loci and Genes for Idiopathic Pulmonary Fibrosis

“…In a recent GWAS in a Japanese population, POT1 was associated with lung cancer [46]. Pulmonary fibrosis patients carrying POT1 variants had shorter telomeres, which led to a worse outcome of IPF [47][48][49]. This suggests that POT1 variants might be involved in the process of shortened telomeres and lead to worse outcomes in IPF.…”

The Role of Telomerase and Telomeres in Interstitial Lung Diseases: From Molecules to Clinical Implications

“…ATM (ataxia-telangiectasia mutated) protein is a dsDNA break response factor that activates a multitude of signal cascades and is known to participate in telomere maintenance via telomerase activation [85]. Although it has been shown to be activated in pathological conditions, including IPF [86,87], the details of its part in fibroblast survival and proliferation under ILDs are also lacking at present. It can be surmised that oxidative stress, which frequently accompanies pulmonary fibrosis, is one of the causes of the observed upregulation of ATM; however, the differences of this process in epithelial and mesenchymal cell populations of the diseased lung still need to be revealed.…”

A homozygous mutation in the highly conserved Tyr60 of the mature IGF1 peptide broadens the spectrum of IGF1 deficiency

“…Infinium CytoSNP-850K SNP array (Illumina) was used to perform aCGH-SNP in the proband's sample. IGF1 exons, intron/exon boundaries and known regulatory regions were PCR amplified and analyzed by high-resolution melting, as previously described (22). Fragments displaying abnormal melting pattern were sequenced with specific oligonucleotides in an ABI 3500 DNA analyzer.…”