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Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia.

Jaako, Pekka LU ; Flygare, Johan LU ; Olsson, Karin LU ; Quere, Ronan LU ; Ehinger, Mats LU ; Henson, Adrianna; Ellis, Steven; Schambach, Axel; Baum, Christopher and Richter, Johan LU , et al. (2011) In Blood 118. p.6087-6096
Abstract
Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Among these genes, ribosomal protein S19 (RPS19) is mutated most frequently. Generation of animal models for diseases like DBA is challenging since the phenotype is highly dependent on the level of RPS19 downregulation. We report the generation of mouse models for RPS19-deficient DBA using transgenic RNA interference that allows an inducible and graded downregulation of Rps19. Rps19-deficient mice develop a macrocytic anemia together with leukocytopenia and variable platelet count that with time leads to the exhaustion of hematopoietic stem cells and bone marrow failure. Both RPS19 gene... (More)
Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Among these genes, ribosomal protein S19 (RPS19) is mutated most frequently. Generation of animal models for diseases like DBA is challenging since the phenotype is highly dependent on the level of RPS19 downregulation. We report the generation of mouse models for RPS19-deficient DBA using transgenic RNA interference that allows an inducible and graded downregulation of Rps19. Rps19-deficient mice develop a macrocytic anemia together with leukocytopenia and variable platelet count that with time leads to the exhaustion of hematopoietic stem cells and bone marrow failure. Both RPS19 gene transfer and the loss of p53 rescue the DBA phenotype implying the potential of the models for testing novel therapies. This study demonstrates the feasibility of transgenic RNA interference to generate mouse models for human diseases caused by haploinsufficient expression of a gene. (Less)
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published
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Blood
volume
118
pages
6087 - 6096
publisher
American Society of Hematology
external identifiers
  • wos:000297757700018
  • pmid:21989989
  • scopus:82955222912
ISSN
1528-0020
DOI
10.1182/blood-2011-08-371963
language
English
LU publication?
yes
id
9d0efffd-7f6d-4e99-9c93-b2617d672c4d (old id 2200600)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21989989?dopt=Abstract
date added to LUP
2011-11-02 09:53:07
date last changed
2017-11-19 04:18:31
@article{9d0efffd-7f6d-4e99-9c93-b2617d672c4d,
  abstract     = {Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Among these genes, ribosomal protein S19 (RPS19) is mutated most frequently. Generation of animal models for diseases like DBA is challenging since the phenotype is highly dependent on the level of RPS19 downregulation. We report the generation of mouse models for RPS19-deficient DBA using transgenic RNA interference that allows an inducible and graded downregulation of Rps19. Rps19-deficient mice develop a macrocytic anemia together with leukocytopenia and variable platelet count that with time leads to the exhaustion of hematopoietic stem cells and bone marrow failure. Both RPS19 gene transfer and the loss of p53 rescue the DBA phenotype implying the potential of the models for testing novel therapies. This study demonstrates the feasibility of transgenic RNA interference to generate mouse models for human diseases caused by haploinsufficient expression of a gene.},
  author       = {Jaako, Pekka and Flygare, Johan and Olsson, Karin and Quere, Ronan and Ehinger, Mats and Henson, Adrianna and Ellis, Steven and Schambach, Axel and Baum, Christopher and Richter, Johan and Larsson, Jonas and Bryder, David and Karlsson, Stefan},
  issn         = {1528-0020},
  language     = {eng},
  pages        = {6087--6096},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia.},
  url          = {http://dx.doi.org/10.1182/blood-2011-08-371963},
  volume       = {118},
  year         = {2011},
}