Deficiency of ribosomal protein S19 in CD34+ cells generated by siRNA blocks erythroid development and mimics defects seen in Diamond-Blackfan anemia

Flygare, Johan; Kiefer, Thomas; Miyake, Keisuke; Utsugisawa, Taiju; Hamaguchi, Isao; Costa, Lydie Da; Richter, Johan; Davey, Edward J.; Matsson, Hans; Dahl, Niklas; Wiznerowicz, Maciej; Trono, Didier; Karlsson, Stefán

doi:10.1182/blood-2004-08-3115

Cited by 111 publications

(109 citation statements)

References 33 publications

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“…Using antibodies specific to CD71, we isolated a population of cells expressing high levels of the CD71 surface protein (CD71 high ), which are enriched for immature erythroid cells. 15,42 Consistent with the low levels of erythroid progenitor cells in DBA patients, [1][2][3] we isolated fewer CD71 high cells from each of the five DBA samples than from the ten normal samples (data not shown). Using PCR and primers specific to FLVCR1 TM 1 and 12 ( Figure 3…”

Section: Isolation Of Alternatively Spliced Flvcr1 Isoforms From Diammentioning

confidence: 74%

“…5,[8][9][10] Approximately 25% of DBA patients have mutations in the gene encoding the S19 ribosomal protein (RPS19), 11,12 which is one of 33 ribosomal proteins that make up the 40S ribosomal subunit that is involved in translation. 13 Down-regulation of RPS19 in CD34 + human hematopoietic stem cells disrupts erythroid progenitor cell but not myeloid cell development, 14,15 which mimics the hematologic features observed in DBA. Transfer of the RPS19 gene into RPS19-deficient DBA bone marrow cells increases the number of erythroid progenitor cells, 16 which clearly demonstrates the importance of RPS19 in erythropoiesis.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis

Rey¹,

Duffy²,

Brown³

et al. 2008

Haematologica

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Section: Isolation Of Alternatively Spliced Flvcr1 Isoforms From Diammentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis

Rey¹,

Duffy²,

Brown³

et al. 2008

Haematologica

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“…on March 28, 2019. by guest www.bloodjournal.org From using RNA interference in primary human hematopoietic progenitor cells from normal persons causes a severe defect in the differentiation and proliferation of erythroid progenitor cells. 81,82 Similarly, primary CD34 ϩ cells from DBA patients have a higher number of apoptotic cells compared with normal CD34 ϩ cells, 83 and mononuclear cells derived from patients with DBA fail to proliferate in response to erythropoietin and form smaller erythroid colonies in methylcellulose compared with normal patients. 84 The hematopoietic defect caused by RPS19 deficiency can be rescued by forced overexpression of RPS19.…”

mentioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

691

726

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Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, SchwachmanDiamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q؊ syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases. Identification of ribosomal abnormalities in human diseaseIn 1999, Draptchinskaia et al reported recurrent mutations in a ribosomal protein gene, RPS19, in patients with Diamond-Blackfan anemia (DBA), a rare congenital bone marrow failure syndrome with a striking erythroid defect. 1 Since that initial discovery, mutations in a number of ribosomal proteins have been identified in up to 50% of patients with DBA. Moreover, other congenital syndromes have been linked to defective ribosome biogenesis, including Schwachman-Diamond syndrome (SDS), X-linked dyskeratosis congenita (DKC), cartilage hair hypoplasia (CHH), and Treacher Collins syndrome (TCS). 2 In the 5qϪ syndrome, a subtype of adult myelodysplastic syndrome, acquired haploinsufficiency for RPS14 resulting from an interstitial chromosomal deletion causes a severe refractory anemia. 3 Each of these disorders is associated with specific defects in ribosome biogenesis, which cause distinct clinical phenotypes, most often involving bone marrow failure and/or craniofacial or other skeletal defects. The disorders of ribosome dysfunction have become collectively known as ribosomopathies. Overview of ribosome biogenesisThe eukaryotic ribosome is composed of 40S and 60S subunits, which associate to form the translationally active 80S ribosome. This process requires the coordinated synthesis of 4 ribosomal RNAs (rRNAs), approximately 80 core ribosomal proteins, more than 150 associated proteins, and approximately 70 small nucleolar RNAs (snoRNAs). 4,5 The 40S subunit contains 18S rRNA and the 60S subunit contains 28S, 5.8S, and 5S rRNAs. In eukaryotes, assembly of rRNA and ribosomal proteins, along with assoc...

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“…It is known, however, that a defect in ribosomal protein S19 blocks red blood cell development [25]. The S19 gene is one of eight ribosomal M8 motif harboring genes, including RPL10A, RPL12, RPL17, RPL26, RPS15A, RPS19, RPS6 and RPS7.…”

Section: Potential Role Of M8 Motif In Erythrocyte Developmentmentioning

confidence: 99%

“…Target ions selected for MS/MS were dynamically excluded for 90 s. The general mass spectrometric conditions were: spray voltage, 2.3 kV; no sheath and auxiliary gas flow; capillary temperature, 160°C; normalized collision energy 35.0, ion selection thresholds were 500 counts for MS/MS acquisition, applying an activation q = 0. 25 and an activation time of 30 ms.…”

Section: Liquid Chromatography Mass Spectrometrymentioning

confidence: 99%

SILAC-Based Quantitative Proteomics Approach to Identify Transcription Factors Interacting with a Novel Cis-Regulatory Element

Trung

Engelke

Mittler

2014

J Proteomics Bioinform

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Deficiency of ribosomal protein S19 in CD34+ cells generated by siRNA blocks erythroid development and mimics defects seen in Diamond-Blackfan anemia

Abstract: Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia in which 25% of the patients have a mutation in the ribosomal protein S19 (RPS19) gene. To study effects of RPS19 deficiency in hematopoiesis we transduced CD34 ؉ umbilical cord blood (CB) and bone marrow (

Cited by 111 publications

References 33 publications

Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis

Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis

Ribosomopathies: human disorders of ribosome dysfunction

SILAC-Based Quantitative Proteomics Approach to Identify Transcription Factors Interacting with a Novel Cis-Regulatory Element

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