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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1582-1592.
Prepublished online as a Blood First Edition Paper on June 5, 2008; DOI 10.1182/blood-2008-02-140012.
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Submitted February 20, 2008
Accepted April 22, 2008
Abnormalities of the large ribosomal subunit protein, Rpl35A, in diamond-blackfan anemia
Jason E. Farrar, Michelle Nater, Emi Caywood, Michael A. McDevitt, Jeanne Kowalski, Clifford M. Takemoto, C Conover Talbot Jr., Paul Meltzer, Diane Esposito, Alan H. Beggs, Hal E. Schneider, Agnieszka Grabowska, Sarah E. Ball, Edyta Niewiadomska, Colin A. Sieff, Adrianna Vlachos, Eva Atsidaftos, Steven R. Ellis, Jeffrey M. Lipton, Hanna T. Gazda, and Robert J. Arceci*
Division of Pediatric Oncology, Dept of Oncology, Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
Division of Hematology, Dept of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
Division of Oncology Biostatistics, Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
Division of Pediatric Hematology, Dept of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States
Division of Genetics and Program in Genomics, Children's Hospital Boston, Boston, MA, United States
Department of Cellular and Molecular Medicine, St.George's University of London, London, United Kingdom
Department of Paediatric Haematology/Oncology, University Medical School, Warsaw, Poland
Division of Pediatric Hematology, Children's Hospital Boston, Boston, MA, United States
Division of Hematology/Oncology and Stem Cell Transplantation, Schneider Children's Hospital, New Hyde Park, NY, United States
Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY, United States
* Corresponding author; email: arcecro{at}jhmi.edu.
Diamond-Blackfan anemia 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 utilized a candidate gene strategy combining high-resolution genomic mapping and gene expression microarray in the analysis of two 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 due to altered ribosomal function. The results also establish that haploinsufficency of large ribosomal subunit proteins contribute to bone marrow failure and potentially cancer predisposition.
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