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Human Molecular Genetics Advance Access published online on January 29, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn015
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Mutation of ribosomal protein RPS24 in Diamond-Blackfan anemia results in a ribosome biogenesis disorder

Valérie Choesmel1,2, Sébastien Fribourg3,4, Almass-Houd Aguissa-Touré1,2, Noël Pinaud3,4, Pierre Legrand5, Hanna T. Gazda6,7 and Pierre-Emmanuel Gleizes1,2,*

1 Université de Toulouse, Laboratoire de Biologie Moléculaire Eucaryote, 31062 Toulouse, France 2 CNRS, UMR 5599, 31062 Toulouse, France 3 INSERM U869, Institut Européen de Chimie et Biologie, F-33607, France. 4 Université Victor Segalen, Bordeaux 2, F-33076,  France. 5 Synchrotron SOLEIL, 91192 Gif sur Yvette Cedex, France. 6 Children's Hospital Boston, Division of Genetics and Program in Genomics, Boston, MA, USA 7 Harvard Medical School, Boston, MA, USA

* Correspondence to: Pierre-Emmanuel Gleizes, LBME-CNRS, 118 route de Narbonne, F- 31062 Toulouse cedex, Phone: +33-561 335 926Fax: +33-561 335 886 gleizes{at}ibcg.biotoul.fr

Received November 12, 2007; Revised January 10, 2008; Accepted January 16, 2008

Diamond-Blackfan anemia (DBA) is a rare congenital disease affecting erythroid precursor differentiation. Remarkably, 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 with RPS19 involvement in maturation of the internal transcribed spacer 1, RPS24 is required for processing of the 5’ external transcribed spacer (5’-ETS). Remarkably, epistasis experiments with siRNAs 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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