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

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...

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Detalhes bibliográficos
Autores: Arias-Salgado, E. G., Galvez, E., Planas-Cerezales, L., Pintado-Berninches, L., Vallespin, E., Martinez, P., Carrillo, J., Iarriccio, L., Ruiz-Llobet, A., Catala, A., Badell-Serra, I., Gonzalez-Granado, L. I., Martin-Nalda, A., Martinez-Gallo, M., Galera-Minarro, A., Rodriguez-Vigil, C., Bastos-Oreiro, M., de Nanclares, G. P., Leiro Fernández, Virginia, Uria, M. L., Diaz-Heredia, C., Valenzuela, C., Martin, S., Lopez-Muniz, B., Lapunzina, P., Sevilla, J., Molina-Molina, M., Perona, R., Sastre, L.
Tipo de documento: artigo
Data de publicação:2019
País:España
Recursos:Servizo Galego de Saúde (SERGAS)
Repositório:RUNA. Repositorio da Consellería de Sanidade e Sergas
OAI Identifier:oai:runa.sergas.gal:20.500.11940/15994
Acesso em linha:https://www.ncbi.nlm.nih.gov/pubmed/30995915
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471801/pdf/13023_2019_Article_1046.pdf
http://hdl.handle.net/20.500.11940/15994
Access Level:Acceso aberto
Palavra-chave:Pulmonary Fibrosis
Adult
Exons
Anemia
Adolescent
Dyskeratosis Congenita
RNA
Telomere
Pedigree
Humans
DNA Repair
Young Adult
Telomerase
Telomere Shortening
Infant
anemia
disqueratosis congénita
exones
adulto
ARN
adulto joven
acortamiento telomérico
humanos
lactante
fibrosis pulmonar
linaje
reparación del ADN
telómero
telomerasa
adolescente
CHUVI
Descrição
Resumo: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.

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