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Draptchinskaia, N. et al. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat. Genet. 21, 169-175

Department of Genetics and Pathology, Uppsala University, Sweden.
Nature Genetics (Impact Factor: 29.65). 03/1999; 21(2):169-75. DOI: 10.1038/5951
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ABSTRACT Diamond-Blackfan anaemia (DBA) is a constitutional erythroblastopenia characterized by absent or decreased erythroid precursors. The disease, previously mapped to human chromosome 19q13, is frequently associated with a variety of malformations. To identify the gene involved in DBA, we cloned the chromosome 19q13 breakpoint in a patient with a reciprocal X;19 chromosome translocation. The breakpoint occurred in the gene encoding ribosomal protein S19. Furthermore, we identified mutations in RPS19 in 10 of 40 unrelated DBA patients, including nonsense, frameshift, splice site and missense mutations, as well as two intragenic deletions. These mutations are associated with clinical features that suggest a function for RPS19 in erythropoiesis and embryogenesis.

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Available from: Joakim Klar, Aug 04, 2014
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    • "In DBA, mutations in RP genes include RPS7, RPS10, RPS17, RPS19, RPS24, RPS26 and RPS29 (encoding RP for the small subunit) and RPL5, RPL11, RPL26 and RPL35A (encoding RP for the large subunit ). These mutations have been reported in up to 60% of DBA patients (Draptchinskaia et al, 1999; Gazda et al, 2006, 2008, 2012; Cmejla et al, 2007; Farrar et al, 2008; Doherty et al, 2010; Konno et al, 2010; Gerrard et al, 2013; Mirabello et al, 2014). To date, approximately 40% of patients have no known pathogenic mutation. "
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    ABSTRACT: Diamond-Blackfan anaemia is a congenital bone marrow failure syndrome that is characterized by red blood cell aplasia. The disease has been associated with mutations or large deletions in 11 ribosomal protein genes including RPS7, RPS10, RPS17, RPS19, RPS24, RPS26, RPS29, RPL5, RPL11, RPL26 and RPL35A as well as GATA1 in more than 50% of patients. However, the molecular aetiology of many Diamond-Blackfan anaemia cases remains to be uncovered. To identify new mutations responsible for Diamond-Blackfan anaemia, we performed whole-exome sequencing analysis of 48 patients with no documented mutations/deletions involving known Diamond-Blackfan anaemia genes except for RPS7, RPL26, RPS29 and GATA1. Here, we identified a de novo splicing error mutation in RPL27 and frameshift deletion in RPS27 in sporadic patients with Diamond-Blackfan anaemia. In vitro knockdown of gene expression disturbed pre-ribosomal RNA processing. Zebrafish models of rpl27 and rps27 mutations showed impairments of erythrocyte production and tail and/or brain development. Additional novel mutations were found in eight patients, including RPL3L, RPL6, RPL7L1T, RPL8, RPL13, RPL14, RPL18A and RPL31. In conclusion, we identified novel germline mutations of two ribosomal protein genes responsible for Diamond-Blackfan anaemia, further confirming the concept that mutations in ribosomal protein genes lead to Diamond-Blackfan anaemia. © 2014 John Wiley & Sons Ltd.
    British Journal of Haematology 11/2014; 168(6). DOI:10.1111/bjh.13229 · 4.96 Impact Factor
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    • "Of the candidate genes, haploinsufficiency was evident in secreted protein acidic and rich in cysteine (SPARC), a tumor suppressor gene, and ribosomal processing S14 gene [RPS14 (component of 40S ribosomal subunit)]. RPS14 haploinsufficiency was of particular interest given that RPS19 mutations represent the most common genetic mutation in patients with Diamond–Blackfan anemia (DBA), a congenital bone marrow failure syndrome with profound erythroid hypoplasia (20). Furthermore, Gazda et al. (21) had shown that haploinsufficiency of RPS19 was the underlying defect in a proportion of patients with DBA (21). "
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    ABSTRACT: Myelodysplastic syndromes (MDS) represent a hematologically diverse group of myeloid neoplasms, however, one subtype characterized by an isolated deletion of chromosome 5q (del(5q)) is pathologically and clinically distinct. Patients with del(5q) MDS share biological features that account for the profound hypoplastic anemia and unique sensitivity to treatment with lenalidomide. Ineffective erythropoiesis in del(5q) MDS arises from allelic deletion of the ribosomal processing S-14 (RPS14) gene, which leads to MDM2 sequestration with consequent p53 activation and erythroid cell death. Since its approval in 2005, lenalidomide has changed the natural course of the disease. Patients who achieve transfusion independence and/or a cytogenetic response with lenalidomide have a decreased risk of progression to AML and an improved overall survival compared to non-responders. Elucidation of the mechanisms of action of lenalidomide in del(5q) MDS has advanced therapeutic strategies for this disease. The selective cytotoxicity of lenalidomide in del(5q) clones derives from inhibition of a haplodeficient phosphatase whose catalytic domain is encoded within the common deleted region on chromosome 5q, i.e., protein phosphatase 2A (PP2Acα). PP2A is a highly conserved, dual specificity phosphatase that plays an essential role in regulation of the G2/M checkpoint. Inhibition of PP2Acα results in cell cycle arrest and apoptosis in del(5q) cells. Targeted knockdown of PP2Acα using siRNA is sufficient to sensitize non-del(5q) clones to lenalidomide. Through its inhibitory effect on PP2A, lenalidomide stabilizes MDM2 to restore p53 degradation in erythroid precursors, with subsequent arrest in G2/M. Unfortunately, the majority of patients with del(5q) MDS develop resistance to lenalidomide over time associated with PP2Acα overexpression. Targeted inhibition of PP2A with a more potent inhibitor has emerged as an attractive therapeutic approach for patients with del(5q) MDS.
    Frontiers in Oncology 09/2014; 4:264. DOI:10.3389/fonc.2014.00264
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    • "To date eleven genes encoding ribosomal proteins have been found mutated in DBA patients, i.e. RPS19, RPS24, RPS17, RPL5, RPL11, RPS7, RPL35A, RPS26, RPS10, RPL26, and RPL15 (Boria et al., 2010; Draptchinskaia et al., 1999; Gazda et al., 2012; Landowski et al., 2013; Quarello et al., 2010). "
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    ABSTRACT: Defects in genes encoding ribosomal proteins cause Diamond Blackfan Anemia (DBA), a red cell aplasia often associated with physical abnormalities. Other bone marrow failure syndromes have been attributed to defects in ribosomal components but the link between erythropoiesis and the ribosome remains to be fully defined. Several lines of evidence suggest that defects in ribosome synthesis lead to “ribosomal stress” with p53 activation and either cell cycle arrest or induction of apoptosis. Pathways independent of p53 have also been proposed to play a role in DBA pathogenesis. We took an unbiased approach to identify p53-independent pathways activated by defects in ribosome synthesis by analyzing global gene expression in various cellular models of DBA. Ranking-Principal Component Analysis (Ranking-PCA) was applied to the identified datasets to determine whether there are common sets of genes whose expression is altered in these different cellular models. We observed consistent changes in the expression of genes involved in cellular amino acid metabolic process, negative regulation of cell proliferation and cell redox homeostasis. These data indicate that cells respond to defects in ribosome synthesis by changing the level of expression of a limited subset of genes involved in critical cellular processes. Moreover, our data support a role for p53-independent pathways in the pathophysiology of DBA.
    Gene 07/2014; 545(2):282–289. · 2.08 Impact Factor
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