title: Impaired ribosome biogenesis in Diamond-Blackfan anemia.
abstract: The gene encoding the ribosomal protein S19 (RPS19) is frequently mutated in Diamond-Blackfan anemia (DBA), a congenital erythroblastopenia. The consequence of these mutations on the onset of the disease remains obscure. Here, we show that RPS19 plays an essential role in biogenesis of the 40S small ribosomal subunit in human cells. Knockdown of RPS19 expression by siRNAs impairs 18S rRNA synthesis and formation of 40S subunits and induces apoptosis in HeLa cells. Pre-rRNA processing is altered, which leads to an arrest in the maturation of precursors to the 18S rRNA. Under these conditions, pre-40S particles are not exported to the cytoplasm and accumulate in the nucleoplasm of the cells in perinuclear dots. Consistently, we find that ribosome biogenesis and nucleolar organization is altered in skin fibroblasts from DBA patients bearing mutations in the RPS19 gene. In addition, maturation of the 18S rRNA is also perturbed in cells from a patient bearing no RPS19-related mutation. These results support the hypothesis that DBA is directly related to a defect in ribosome biogenesis and indicate that yet to be discovered DBA-related genes may be involved in the synthesis of the ribosomal subunits.
authors.affiliation: Laboratoire de Biologie Moléculaire des Eucaryotes, Unite Mixte de Recherche 5099, Institut d'Exploration Fonctionnelle des Génomes, CNRS, and Université Paul Sabatier, Toulouse, and Service d'oncologie-pédiatrie, Hôpital Saint-Louis, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Choesmel
authors.forename: Daniel
authors.initials: D
authors.lastname: Bacqueville
authors.forename: Jacques
authors.initials: J
authors.lastname: Rouquette
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Noaillac-Depeyre
authors.forename: Sébastien
authors.initials: S
authors.lastname: Fribourg
authors.forename: Aurore
authors.initials: A
authors.lastname: Crétien
authors.forename: Thierry
authors.initials: T
authors.lastname: Leblanc
authors.forename: Gil
authors.initials: G
authors.lastname: Tchernia
authors.forename: Lydie
authors.initials: L
authors.lastname: Da Costa
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Gleizes
mesh_terms: D029503:Anemia, Diamond-Blackfan / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D012337:RNA, Ribosomal, 18S / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000494:pharmacology; D012269:Ribosomal Proteins / Q000235:genetics*; D012270:Ribosomes / Q000378:metabolism*
chemical_list: D012337:RNA, Ribosomal, 18S; D034741:RNA, Small Interfering; D012269:Ribosomal Proteins; C040343:ribosomal protein S19