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, Català-Temprano A, Badell-Serra I, Gonzalez-Granado LI, Martín-Nalda A, Martínez-Gallo M, Galera-Miñarro A, Rodríguez-Vigil C, Bastos-Oreiro M, Perez de Nanclares G, Leiro-Fernández V, Uria ML, Diaz-Heredia C, Valenzuela C, Martín S, López-Muñiz B, Lapunzina P, Sevilla J, Molina-Molina M, Perona R and Sastre L
Publicada:
17 abr 2019
Ahead of Print:
17 abr 2019
Resumen:
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.
Filiaciones:
Arias-Salgado EG:
Instituto de Investigaciones Biomedicas CSIC/UAM, IDIPaz, Arturo Duperier, 4, 28029, Madrid, Spain
Advanced Medical Projects, Madrid, Spain
Galvez E:
Hospital Niño Jesús, Hematología y Hemoterapia, Madrid, Spain
Planas-Cerezales L:
ILD Unit Pneumology Department, University Hospital of Bellvitge, IDIBELL, University of Barcelona, Barcelona, Spain
Pintado-Berninches L:
Instituto de Investigaciones Biomedicas CSIC/UAM, IDIPaz, Arturo Duperier, 4, 28029, Madrid, Spain
Advanced Medical Projects, Madrid, Spain
Vallespin E:
Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Madrid, Spain
Martinez P:
Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Madrid, Spain
Carrillo J:
Instituto de Investigaciones Biomedicas CSIC/UAM, IDIPaz, Arturo Duperier, 4, 28029, Madrid, Spain
Iarriccio L:
Instituto de Investigaciones Biomedicas CSIC/UAM, IDIPaz, Arturo Duperier, 4, 28029, Madrid, Spain
Advanced Medical Projects, Madrid, Spain
Ruiz-Llobet A:
Pediatric Hematology and Oncology Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
Institut de Recerca Pediàtrica Hospital Sant Joan de Déu (IRP-HSJD), Esplugues de Llobregat, Barcelona, Spain
Català-Temprano A:
Pediatric Hematology and Oncology Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
Institut de Recerca Pediàtrica Hospital Sant Joan de Déu (IRP-HSJD), Esplugues de Llobregat, Barcelona, Spain
Badell-Serra I:
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Gonzalez-Granado LI:
Hospital 12 de Octubre, Madrid, Spain
Martín-Nalda A:
Immunology Division, Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Barcelona, Spain
Martínez-Gallo M:
Immunology Division, Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Barcelona, Spain
Galera-Miñarro A:
Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
Rodríguez-Vigil C:
Hospital Miguel Servet, Zaragoza, Spain
Bastos-Oreiro M:
Hospital Universitario Gregorio Marañon, IiSGM, Madrid, Spain
Perez de Nanclares G:
Molecular (Epi)Genetics Laboratory, BioAraba National Health Institute, OSI Araba University Hospital, Vitoria-Gasteiz, Spain
Leiro-Fernández V:
Pneumology Department, Hospital Álvaro Cunqueiro, Complexo Hospitalario Universitario de Vigo, NeumoVigoI+i Research Group, Vigo Biomedical Research Institute (IBIV), Barcelona, Spain
Uria ML:
Immunology Division, Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Barcelona, Spain
Diaz-Heredia C:
Immunology Division, Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Barcelona, Spain
Valenzuela C:
Hospital de La Princesa, Madrid, Spain
Martín S:
ILD Unit Pneumology Department, University Hospital of Bellvitge, IDIBELL, University of Barcelona, Barcelona, Spain
López-Muñiz B:
Hospital Infanta Leonor, Madrid, Spain
Lapunzina P:
Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Madrid, Spain
CIBER de enfermedades raras (CIBERER), Madrid, Spain
Sevilla J:
Hospital Niño Jesús, Hematología y Hemoterapia, Madrid, Spain
CIBER de enfermedades raras (CIBERER), Madrid, Spain
Molina-Molina M:
ILD Unit Pneumology Department, University Hospital of Bellvitge, IDIBELL, University of Barcelona, Barcelona, Spain
CIBER of Respiratory diseases (CIBERES), Barcelona, Spain
Perona R:
Instituto de Investigaciones Biomedicas CSIC/UAM, IDIPaz, Arturo Duperier, 4, 28029, Madrid, Spain
CIBER de enfermedades raras (CIBERER), Madrid, Spain
Sastre L:
Instituto de Investigaciones Biomedicas CSIC/UAM, IDIPaz, Arturo Duperier, 4, 28029, Madrid, Spain.
CIBER de enfermedades raras (CIBERER), Madrid, Spain.
Open Access
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