Diamond-Blackfan anemia (DBA) typically presents with red blood cell aplasia that usually manifests in the first year of life. The only gene currently known to be mutated in DBA encodes ribosomal protein S19 (RPS19). Previous studies have shown that the yeast RPS19 protein is required for a specific step in the maturation of 40S ribosomal subunits. Our objective here was to determine whether the human RPS19 protein functions at a similar step in 40S subunit maturation. Studies where RPS19 expression is reduced by siRNA in the hematopoietic cell line, TF-1, show that human RPS19 is also required for a specific step in the maturation of 40S ribosomal subunits. This maturation defect can be monitored by studying rRNA-processing intermediates along the ribosome synthesis pathway. Analysis of these intermediates in CD34 ؊ cells from the bone marrow of patients with DBA harboring mutations in RPS19 revealed a pre-rRNA-processing defect similar to that observed in TF-1 cells where RPS19 expression was reduced. This defect was observed to a lesser extent in CD34 ؉ cells from patients with DBA who have mutations in RPS19. IntroductionDiamond-Blackfan anemia (DBA) typically presents as a red blood cell aplasia that affects children in their first year of life. In addition to anemia, patients with DBA present with a heterogeneous mixture of congenital abnormalities. 1 Craniofacial abnormalities are observed in approximately 50% of patients with DBA, while other defects, including growth failure, thumb malformation, and cardiac and urogenital defects, are observed less frequently.Approximately 25% of patients with DBA have mutations in the gene encoding ribosomal protein S19, 1 of 33 ribosomal proteins that together with 18S rRNA constitutes the 40S ribosomal subunit. [2][3][4] The etiology of the remaining cases of DBA is unknown. DBA is the first and only human disease known to be caused by mutations in a gene encoding a ribosomal protein. Interestingly, several other bone marrow (BM) failure syndromes have been linked to factors involved in ribosome synthesis. 5 These syndromes include dyskeratosis congenita (DC), cartilage hair hypoplasia (CHH), and Shwachman Diamond syndrome (SDS). The proteins and RNAs affected in these diseases include the DKC1 gene in X-linked DC, which encodes a pseudouracil synthase, 6 dyskerin involved in rRNA modification, the gene RMRP involved in CHH, which participates in rRNA processing, 7 and SBDS, the gene affected in SDS which encodes a protein thought to function in RNA metabolism. [8][9][10][11] The exact role of a defect in ribosome synthesis in each of these marrow failure syndromes is obscured by the fact that some of these proteins and RNAs are part of complexes that have multiple functions within cells. Dyskerin is a component of a number of ribonucleoprotein complexes, including telomerase, 12-14 whereas RMRP is a component of an endoribonuclease involved in mRNA decay in addition to rRNA processing. 15 The only other known function for ribosomal protein S19 (RPS19) is as a monoc...
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