|
|
Hematopoietic stem and progenitor cell defects in transgenic model of Diamond-Blackfan anemia
Holečková, Markéta ; Kokavec, Juraj (advisor) ; Valášek, Leoš (referee)
Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome characterized by deficient development of erythroid progenitors and accompanied by a variable set of developmental defects. About 25 % of patients have mutations of the small ribosomal subunit protein RPS19, and the precise mechanism of single aminoacidic mutations of RPS19 protein in the pathology of Diamond-Blackfan anemia remains largely unknown. To understand the interaction between of genotype and phenotypic variability we have created a mouse model with homozygous mutation in a highly conserved arginine 67 (Rps19R67Δ/R67Δ ). Mouse model with this mutation display many of the same phenotypical trades as patients with DBA. We decided to focus on hematopoiesis and erythropoiesis in this mouse model and tried to characterize those processes. We discovered that Rps19R67Δ/R67Δ mice similarly to DBA patients suffer from anemia and that the erythropoiesis process is disrupted at the stage of proerythroblasts. We also observed changes in hematopoiesis in stages as early as multipotent progenitors. The role of p53 protein as a modifier of DBA phenotype is well known. We created mouse model with p53 depletion to assess the role of p53 protein in relation with mutation in Rps19. Rps19R67Δ/R67Δ Trp53-/- mice show no signs of...
|
|
|
Molecular mechanisms of Diamond-Blackfan anemia
Handrková, Helena ; Petrák, Jiří (advisor) ; Šebela, Marek (referee) ; Trka, Jan (referee)
Diamond-Blackfan anemia (DBA) is a rare congenital syndrome that presents with ane- mia and selective deficiency of erythroid precursors, while other blood lineages are usu- ally unaffected. Approximately half of the patients display additional somatic anoma- lies and growth retardation. The therapy is mostly symptomatic and is dominated by corticosteroids, other modalities include regular blood transfusions or hematopoietic stem cell transplantation. At the beginning of this work, only two DBA causal genes were known, RPS19 and RPS24, being mutated in approximately 1/4 of all DBA patients. The goals of this work were to study the consequences of the known DBA causal mutations on cellular level and to find novel DBA causal genes. To date, over a half of DBA patients have been reported to carry a mutation in one of nine known DBA causal genes, including RPS17, RPL11 and RPL5, that are reported in this dissertation. All confirmed DBA causal genes encode for ribosomal proteins (RPs) that were essential for ribosome assembly. We further hypothesized a non- ribosomal protein participating in this process might be involved in DBA pathogenesis, too. In one DBA patient, we identified a rare sequence variant in one such candidate, a protein arginine methyltransferase 3 (PRMT3). We reported that the patient PRMT3...
|
|
| |
|
|
Molecular mechanisms of Diamond-Blackfan anemia
Handrková, Helena ; Petrák, Jiří (advisor) ; Šebela, Marek (referee) ; Trka, Jan (referee)
Diamond-Blackfan anemia (DBA) is a rare congenital syndrome that presents with ane- mia and selective deficiency of erythroid precursors, while other blood lineages are usu- ally unaffected. Approximately half of the patients display additional somatic anoma- lies and growth retardation. The therapy is mostly symptomatic and is dominated by corticosteroids, other modalities include regular blood transfusions or hematopoietic stem cell transplantation. At the beginning of this work, only two DBA causal genes were known, RPS19 and RPS24, being mutated in approximately 1/4 of all DBA patients. The goals of this work were to study the consequences of the known DBA causal mutations on cellular level and to find novel DBA causal genes. To date, over a half of DBA patients have been reported to carry a mutation in one of nine known DBA causal genes, including RPS17, RPL11 and RPL5, that are reported in this dissertation. All confirmed DBA causal genes encode for ribosomal proteins (RPs) that were essential for ribosome assembly. We further hypothesized a non- ribosomal protein participating in this process might be involved in DBA pathogenesis, too. In one DBA patient, we identified a rare sequence variant in one such candidate, a protein arginine methyltransferase 3 (PRMT3). We reported that the patient PRMT3...
|
|
| |
|
| |
|
| |
guest ::
