title: Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia.
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.
authors: Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Lund, Sweden.
authors: Pekka
authors: P
authors: Jaako
authors: Johan
authors: J
authors: Flygare
authors: Karin
authors: K
authors: Olsson
authors: Ronan
authors: R
authors: Quere
authors: Mats
authors: M
authors: Ehinger
authors: Adrianna
authors: A
authors: Henson
authors: Steven
authors: S
authors: Ellis
authors: Axel
authors: A
authors: Schambach
authors: Christopher
authors: C
authors: Baum
authors: Johan
authors: J
authors: Richter
authors: Jonas
authors: J
authors: Larsson
authors: David
authors: D
authors: Bryder
authors: Stefan
authors: S
authors: Karlsson
mesh_terms: D000741:Anemia, Aplastic; D029503:Anemia, Diamond-Blackfan / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000748:Anemia, Macrocytic / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D016026:Bone Marrow Transplantation; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000473:pathology / Q000502:physiology; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D007970:Leukopenia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D010976:Platelet Count; D034741:RNA, Small Interfering / Q000494:pharmacology; D012269:Ribosomal Proteins / Q000172:deficiency / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D012269:Ribosomal Proteins; C531064:Rps19 protein, mouse; D016159:Tumor Suppressor Protein p53