Abstract
BackgroundTelomeres 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.MethodsThis 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.ResultsForty-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.ConclusionNovel 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.
Highlights
Telomeres are nucleoprotein structures present at the terminal region of the chromosomes
Single nucleotide variants in genes related to telomere biology The possible genetic bases of the diseases were studied in patients that presented symptoms related to dyskeratosis congenita (DC), either mucocutaneous symptoms or, more often, aplastic anemia (AA) or sporadic or familial cases of pulmonary fibrosis (PF)
According to previous reports [12, 22], patients with telomere length below the 1 % of the age-mated population in the case of DC and < 10% in AA and PF where included in this study
Summary
Telomeres are nucleoprotein structures present at the terminal region of the chromosomes. Chromosome ends are protected by nucleoprotein structures, the telomeres. Telomere DNA is bound by a protein complex named shelterin [2] and this nucleo-protein structure protects chromosome ends from degradation and is critical for genome stability (recently reviewed in [3]). Telomeres cannot be completely synthesized during DNA replication, which is known as the end-replication problem and results in progressive shortening of the telomeres as cells proliferate. Telomere DNA is elongated after each round of DNA replication by a specialized complex with reverse transcriptase activity known as telomerase [4]. The enzymatic activity of the complex is provided by the TERT (telomerase reverse transcriptase) protein while the RNA component TR (telomerase RNA, encoded by TERC) is used as template. Essential components of the complex are DKC (Dyskeratosis congenita), NOP10, NHP2 and GAR1 proteins, which bind and stabilize TR and are required for telomerase complex assembly [5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
