Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia
Open Access
- 1 September 2008
- journal article
- case report
- Published by American Society of Hematology in Blood
- Vol. 112 (5), 1582-1592
- https://doi.org/10.1182/blood-2008-02-140012
Abstract
Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, congenital abnormalities, and cancer predisposition. Small ribosomal subunit genes RPS19, RPS24, and RPS17 are mutated in approximately one-third of patients. We used a candidate gene strategy combining high-resolution genomic mapping and gene expression microarray in the analysis of 2 DBA patients with chromosome 3q deletions to identify RPL35A as a potential DBA gene. Sequence analysis of a cohort of DBA probands confirmed involvement RPL35A in DBA. shRNA inhibition shows that Rpl35a is essential for maturation of 28S and 5.8S rRNAs, 60S subunit biogenesis, normal proliferation, and cell survival. Analysis of pre-rRNA processing in primary DBA lymphoblastoid cell lines demonstrated similar alterations of large ribosomal subunit rRNA in both RPL35A-mutated and some RPL35A wild-type patients, suggesting additional large ribosomal subunit gene defects are likely present in some cases of DBA. These data demonstrate that alterations of large ribosomal subunit proteins cause DBA and support the hypothesis that DBA is primarily the result of altered ribosomal function. The results also establish that haploinsufficiency of large ribosomal subunit proteins contributes to bone marrow failure and potentially cancer predisposition.This publication has 53 references indexed in Scilit:
- Identification of RPS14 as a 5q- syndrome gene by RNA interference screenNature, 2008
- Ribosomal Protein L33 Is Required for Ribosome Biogenesis, Subunit Joining, and Repression of GCN4 TranslationMolecular and Cellular Biology, 2007
- Cells depleted for RPS19, a protein associated with Diamond Blackfan Anemia, show defects in 18S ribosomal RNA synthesis and small ribosomal subunit productionBlood Cells, Molecules, and Diseases, 2007
- Diamond Blackfan anemia: A paradigm for a ribosome-based diseaseMedical Hypotheses, 2006
- Ribosomal Protein S24 Gene Is Mutated in Diamond-Blackfan AnemiaAmerican Journal of Human Genetics, 2006
- Impaired ribosome biogenesis in Diamond-Blackfan anemiaBlood, 2006
- Human RPS19, the gene mutated in Diamond-Blackfan anemia, encodes a ribosomal protein required for the maturation of 40S ribosomal subunitsBlood, 2006
- An RNA interference model of RPS19 deficiency in Diamond-Blackfan anemia recapitulates defective hematopoiesis and rescue by dexamethasone: identification of dexamethasone-responsive genes by microarrayBlood, 2005
- Deficiency of ribosomal protein S19 in CD34+ cells generated by siRNA blocks erythroid development and mimics defects seen in Diamond-Blackfan anemiaBlood, 2005
- Many Ribosomal Protein Genes Are Cancer Genes in ZebrafishPLoS Biology, 2004