Abnormalities of the large ribosomal subunit protein, Rp135a, in Diamond-Blackfan anemia

Farrar, J. E., Nater, M., Caywood, E., McDevitt, M. A., Kowalski, J., Takemoto, C. M., Talbot, C. C., Meltzer, P., Esposito, D., Beggs, A. H., Schneider, H. E., Grabowska, A., Ball, S. E., Niewiadomska, E., Sieff, C. A., Vlachos, A., Atsidaftos, E., Ellis, S. R., Lipton, J. M., Gazda, H. T., Areci, R. J. (2008) Abnormalities of the large ribosomal subunit protein, Rp135a, in Diamond-Blackfan anemia. Blood, 112 (5). pp. 1582-1592. ISSN 0006-4971

URL: https://www.ncbi.nlm.nih.gov/pubmed/18535205
DOI: 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 Rp135a 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.

Item Type: Paper
Uncontrolled Keywords: SACCHAROMYCES-CEREVISIAE RNA INTERFERENCE GENE RPS19 CELLS IDENTIFICATION EXPRESSION MUTATIONS STRESS S19
Subjects: bioinformatics
bioinformatics > genomics and proteomics > analysis and processing > microarray gene expression processing
bioinformatics > genomics and proteomics > alignment > sequence alignment
bioinformatics > genomics and proteomics > analysis and processing > Sequence Data Processing
organism description > bacteria
diseases & disorders > bone diseses
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations
CSHL Authors:
Communities: CSHL labs
Depositing User: Tom Adams
Date Deposited: 14 Jul 2011 21:01
Last Modified: 14 Mar 2018 14:52
PMCID: PMC2518874
Related URLs:
URI: http://repository.cshl.edu/id/eprint/7731

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