Genetic analyses of aplastic anemia and idiopathic pulmonary fibrosis patients with short telomeres, possible implication of DNA-repair genes
Por:
Arias-Salgado, EG, 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, LI, Martin-Nalda, A, Martinez-Gallo, M, Galera-Minarro, A, Rodriguez-Vigil, C, Bastos-Oreiro, M, de Nanclares, GP, Leiro-Fernandez, V, Uria, ML, Diaz-Heredia, C, Valenzuela, C, Martin, S, Lopez-Muniz, B, Lapunzina, P, Sevilla, J, Molina-Molina, M, Perona, R, Sastre, L
Publicada:
17 abr 2019
Resumen:
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.
Filiaciones:
Arias-Salgado, EG:
CSIC, UAM, IDIPaz, Inst Invest Biomed, Madrid 28029, Spain
Adv Med Projects, Madrid, Spain
Galvez, E:
Hosp Nino Jesus, Hematol & Hemoterapia, Madrid, Spain
Planas-Cerezales, L:
Univ Barcelona, IDIBELL, Univ Hosp Bellvitge, ILD Unit,Pneumol Dept, Barcelona, Spain
Pintado-Berninches, L:
CSIC, UAM, IDIPaz, Inst Invest Biomed, Madrid 28029, Spain
Adv Med Projects, Madrid, Spain
Vallespin, E:
Hosp Univ La Paz, Inst Med & Mol Genet INGEMM, Madrid, Spain
Martinez, P:
Hosp Univ La Paz, Inst Med & Mol Genet INGEMM, Madrid, Spain
Carrillo, J:
CSIC, UAM, IDIPaz, Inst Invest Biomed, Madrid 28029, Spain
Iarriccio, L:
CSIC, UAM, IDIPaz, Inst Invest Biomed, Madrid 28029, Spain
Adv Med Projects, Madrid, Spain
Ruiz-Llobet, A:
Univ Barcelona, Hosp St Joan Deu, Pediat Hematol & Oncol Dept, Barcelona, Spain
HSJD, IRP, Barcelona, Spain
Catala, A:
Univ Barcelona, Hosp St Joan Deu, Pediat Hematol & Oncol Dept, Barcelona, Spain
HSJD, IRP, Barcelona, Spain
Badell-Serra, I:
Hosp Santa Creu & Sant Pau, Barcelona, Spain
Gonzalez-Granado, LI:
Hosp 12 Octubre, Madrid, Spain
Martin-Nalda, A:
Autonomous Univ Barcelona UAB, Dept Cell Biol Physiol & Immunol, Pediat Infect Dis & Immunodeficiencies Unit, HUVH,Vall Hebron Res Inst VHIR,Immunol Unit, Barcelona, Spain
Martinez-Gallo, M:
Autonomous Univ Barcelona UAB, Dept Cell Biol Physiol & Immunol, Pediat Infect Dis & Immunodeficiencies Unit, HUVH,Vall Hebron Res Inst VHIR,Immunol Unit, Barcelona, Spain
Galera-Minarro, A:
Hosp Univ Virgen Arrixaca, Murcia, Spain
Rodriguez-Vigil, C:
Hosp Miguel Servet, Zaragoza, Spain
Bastos-Oreiro, M:
Hosp Univ Gregorio Maranon, IiSGM, Madrid, Spain
de Nanclares, GP:
OSI Araba Univ Hosp, BioAraba Natl Hlth Inst, Mol Epi Genet Lab, Vitoria, Spain
Leiro-Fernandez, V:
Complexo Hosp Univ Vigo, NeumoVigoII Res Grp, Hosp Alvaro Cunqueiro, Pneumol Dept,Vigo Biomed Res Inst IBIV, Barcelona, Spain
Uria, ML:
Autonomous Univ Barcelona UAB, Dept Cell Biol Physiol & Immunol, Pediat Infect Dis & Immunodeficiencies Unit, HUVH,Vall Hebron Res Inst VHIR,Immunol Unit, Barcelona, Spain
Diaz-Heredia, C:
Autonomous Univ Barcelona UAB, Dept Cell Biol Physiol & Immunol, Pediat Infect Dis & Immunodeficiencies Unit, HUVH,Vall Hebron Res Inst VHIR,Immunol Unit, Barcelona, Spain
Valenzuela, C:
Hosp La Princesa, Madrid, Spain
Martin, S:
Univ Barcelona, IDIBELL, Univ Hosp Bellvitge, ILD Unit,Pneumol Dept, Barcelona, Spain
Lopez-Muniz, B:
Hosp Infanta Leonor, Madrid, Spain
Lapunzina, P:
Hosp Univ La Paz, Inst Med & Mol Genet INGEMM, Madrid, Spain
CIBER Enfermedades Raras CIBERER, Madrid, Spain
Sevilla, J:
Hosp Nino Jesus, Hematol & Hemoterapia, Madrid, Spain
CIBER Enfermedades Raras CIBERER, Madrid, Spain
Molina-Molina, M:
Univ Barcelona, IDIBELL, Univ Hosp Bellvitge, ILD Unit,Pneumol Dept, Barcelona, Spain
CIBER Resp Dis CIBERES, Barcelona, Spain
Perona, R:
CSIC, UAM, IDIPaz, Inst Invest Biomed, Madrid 28029, Spain
CIBER Enfermedades Raras CIBERER, Madrid, Spain
Sastre, L:
CSIC, UAM, IDIPaz, Inst Invest Biomed, Madrid 28029, Spain
CIBER Enfermedades Raras CIBERER, Madrid, Spain
Gold, Green Published
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