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

Pekka Jaako; Johan Flygare; Karin Olsson; Ronan Quere; Mats Ehinger; Adrianna Henson; Steven Ellis; Axel Schambach; Christopher Baum; Johan Richter; Jonas Larsson; David Bryder; Stefan Karlsson

doi:10.1182/blood-2011-08-371963

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

Blood. 2011 Dec 1;118(23):6087-96. doi: 10.1182/blood-2011-08-371963. Epub 2011 Oct 11.

Authors

Pekka Jaako¹, Johan Flygare, Karin Olsson, Ronan Quere, Mats Ehinger, Adrianna Henson, Steven Ellis, Axel Schambach, Christopher Baum, Johan Richter, Jonas Larsson, David Bryder, Stefan Karlsson

Affiliation

¹ Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Lund, Sweden.

PMID: 21989989
DOI: 10.1182/blood-2011-08-371963

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 because the phenotype is highly dependent on the level of RPS19 down-regulation. We report the generation of mouse models for RPS19-deficient DBA using transgenic RNA interference that allows an inducible and graded down-regulation 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anemia, Aplastic
Anemia, Diamond-Blackfan / genetics*
Anemia, Diamond-Blackfan / pathology
Anemia, Diamond-Blackfan / physiopathology
Anemia, Macrocytic / genetics
Anemia, Macrocytic / pathology
Anemia, Macrocytic / physiopathology
Animals
Apoptosis / physiology
Bone Marrow Diseases
Bone Marrow Failure Disorders
Bone Marrow Transplantation
Cell Division / physiology
Cells, Cultured
Disease Models, Animal*
Gene Expression / physiology
Hematopoietic Stem Cells / pathology
Hematopoietic Stem Cells / physiology
Hemoglobinuria, Paroxysmal / genetics*
Hemoglobinuria, Paroxysmal / pathology
Hemoglobinuria, Paroxysmal / physiopathology
Leukopenia / genetics
Leukopenia / pathology
Leukopenia / physiopathology
Mice
Mice, Transgenic*
Phenotype
Platelet Count
RNA, Small Interfering / pharmacology
Ribosomal Proteins / deficiency
Ribosomal Proteins / genetics*
Tumor Suppressor Protein p53 / genetics

Substances

RNA, Small Interfering
Ribosomal Proteins
Rps19 protein, mouse
Tumor Suppressor Protein p53