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Ribosomal Protein Genes RPS10 and RPS26 Are Commonly Mutated in Diamond-Blackfan Anemia |
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| Authors: | Leana Doherty Adrianna Vlachos Valerie Choesmel Marie-Françoise O'Donohue Catherine Clinton Colin A Sieff Peter E Newburger Edyta Niewiadomska Bertil Glader Jason E Farrar Jeffrey M Lipton Pierre-Emmanuel Gleizes Hanna T Gazda |
| Institution: | 1 Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, MA 02115, USA 2 Feinstein Institute for Medical Research, Manhasset, NY 11030, USA 3 Schneider Children's Hospital, Albert Einstein College of Medicine, New Hyde Park, NY 11040, USA 4 Universite de Toulouse, UPS, Laboratoire de Biologie Moleculaire Eucaryote, Toulouse F-31000, France 5 CNRS, UMR 5099, Toulouse F-31000, France 6 Division of Pediatric Hematology, Children's Hospital Boston, Boston, MA 02115, USA 7 Harvard Medical School, Boston, MA 02115, USA 8 Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01655, USA 9 Department of Cellular and Molecular Medicine, St. George's University of London, London SW17 ORE, UK 10 Department of Paediatric Haematology and Oncology, Medical University of Warsaw, Warsaw 00-576, Poland 11 Division of Pediatric Hematology/Oncology, Stanford University School of Medicine, Stanford, CA 94304, USA 12 Division of Pediatric Oncology, Department of Oncology, Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA |
| Abstract: | Diamond-Blackfan anemia (DBA), an inherited bone marrow failure syndrome characterized by anemia that usually presents before the first birthday or in early childhood, is associated with birth defects and an increased risk of cancer. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, in particular craniofacial, upper limb, heart, and urinary system defects that are present in ∼30%–50% of patients. DBA has been associated with mutations in seven ribosomal protein (RP) genes, RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, and RPS7, in about 43% of patients. To continue our large-scale screen of RP genes in a DBA population, we sequenced 35 ribosomal protein genes, RPL15, RPL24, RPL29, RPL32, RPL34, RPL9, RPL37, RPS14, RPS23, RPL10A, RPS10, RPS12, RPS18, RPL30, RPS20, RPL12, RPL7A, RPS6, RPL27A, RPLP2, RPS25, RPS3, RPL41, RPL6, RPLP0, RPS26, RPL21, RPL36AL, RPS29, RPL4, RPLP1, RPL13, RPS15A, RPS2, and RPL38, in our DBA patient cohort of 117 probands. We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands. Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA. This accumulation is consistent with the phenotype observed in HeLa cells after knockdown of RPS10 or RPS26 expression with siRNAs, which indicates that mutations in the RPS10 and RPS26 genes in DBA patients affect the function of the proteins in rRNA processing. |
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