Human Molecular Genetics Advance Access originally published online on January 29, 2008
Human Molecular Genetics 2008 17(9):1253-1263; doi:10.1093/hmg/ddn015
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Mutation of ribosomal protein RPS24 in Diamond-Blackfan anemia results in a ribosome biogenesis disorder
1 Laboratoire de Biologie Moléculaire Eucaryote, Université de Toulouse, 31062 Toulouse, France 2 CNRS, UMR 5099, 31062 Toulouse, France 3 INSERM U869, Institut Européen de Chimie et Biologie, F-33607 Pessac, France 4 Université Victor Segalen, Bordeaux 2, F-33076 Bordeaux, France 5 Synchrotron SOLEIL, 91192 Gif sur Yvette Cedex, France 6 Division of Genetics and Program in Genomics, Children’s Hospital Boston, Boston, MA, USA 7 Harvard Medical School, Boston, MA, USA
* To whom correspondence should be addressed at: LBME-CNRS, 118 route de Narbonne, F-31062 Toulouse Cedex, France. Tel: +33 561335926; Fax: +33 561335886; Email: gleizes{at}ibcg.biotoul.fr
Received November 12, 2007; Accepted January 16, 2008
Diamond-Blackfan anemia (DBA) is a rare congenital disease affecting erythroid precursor differentiation. DBA is emerging as a paradigm for a new class of pathologies potentially linked to disorders in ribosome biogenesis. Three genes encoding ribosomal proteins have been associated to DBA: after RPS19, mutations in genes RPS24 and RPS17 were recently identified in a fraction of the patients. Here, we show that cells from patients carrying mutations in RPS24 have defective pre-rRNA maturation, as in the case of RPS19 mutations. However, in contrast to RPS19 involvement in the maturation of the internal transcribed spacer 1, RPS24 is required for processing of the 5' external transcribed spacer. Remarkably, epistasis experiments with small interfering RNAs indicate that the functions of RPS19 and RPS24 in pre-rRNA processing are connected. Resolution of the crystal structure of RPS24e from the archeon Pyroccocus abyssi reveals domains of RPS24 potentially involved in interactions with pre-ribosomes. Based on these data, we discuss the impact of RPS24 mutations and speculate that RPS19 and RPS24 cooperate at a particular stage of ribosome biogenesis connected to a cell cycle checkpoint, thus affecting differentiation of erythroid precursors as well as developmental processes.
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