Human Molecular Genetics Advance Access published online on May 20, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm120
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Missense mutations associated to Diamond-Blackfan Anemia affect the assembly of ribosomal protein S19 into the ribosome
1 Department of Biology, University "Tor Vergata", Roma, Italy 00133 2 Istituto di Neuroscienze Sperimentali, Fondazione Santa Lucia, Rome, Italy 00179 3 Department of Medical Sciences and Interdisciplinary Research Centre of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Italy 28100
To whom correspondence should be addressed: Fabrizio Loreni, Department of Biology, University "Tor Vergata" 00133 Roma, Italy. Tel.: +39 0672594317; Fax: +39 062023500; E-mail: loreni{at}uniroma2.it
Received March 1, 2006; Revised April 27, 2007; Accepted April 27, 2007
RPS19 has been identified as the first gene associated to Diamond-Blackfan anemia (DBA), a rare congenital hypoplastic anemia that includes variable physical malformations. It is mutated in about 25% of the patients although doubts remain as to whether DBA clinical phenotype depends on the ribosomal function of RPS19 or on an extra-ribosomal role or on both. RPS19 mRNAs with mutations which introduce premature stop codons or eliminate it are rapidly turned over by the surveillance mechanisms possibly causing a decrease in the RPS19 protein level. A decrease in RPS19 level has been shown to cause a defect in the maturation of 18S rRNA. Less clear is the effect of missense mutations in RPS19. With the aim of analyzing the functional features of mutated RPS19, we prepared cDNA constructs expressing RPS19 containing 11 missense mutations and a trinucleotide insertion found in DBA patients. After transfection we analyzed the following properties of the mutated proteins: i) protein stability, ii) subcellular localization, iii) assembly into ribosomes. Our results indicate that some RPS19 mutations alter the capacity of the protein to localize in nucleolar structure and these mutated RPS19 are very unstable. Moreover none of the mutated RPS19 analyzed in this study, including those proteins that appear localized into the nucleolus, is able to be assembled into mature ribosome.
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