Human Molecular Genetics Advance Access originally published online on May 20, 2007
Human Molecular Genetics 2007 16(14):1720-1727; doi:10.1093/hmg/ddm120
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Missense mutations associated with 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 00143 and 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 at: Department of Biology, University ‘Tor Vergata’, Roma 00133, Italy. Tel: +39 0672594317; Fax: +39 062023500; E-mail: loreni{at}uniroma2.it
Received March 1, 2007; Accepted April 27, 2007
RPS19 has been identified as the first gene associated with Diamond–Blackfan anemia (DBA), a rare congenital hypoplastic anemia that includes variable physical malformations. It is mutated in 
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 that 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 ribosomal RNA. 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 and (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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  V. Choesmel, S. Fribourg, A.-H. Aguissa-Toure, N. Pinaud, P. Legrand, H. T. Gazda, and P.-E. Gleizes Mutation of ribosomal protein RPS24 in Diamond-Blackfan anemia results in a ribosome biogenesis disorder Hum. Mol. Genet., May 1, 2008; 17(9): 1253 - 1263. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Gregory, A.-H. Aguissa-Toure, N. Pinaud, P. Legrand, P.-E. Gleizes, and S. Fribourg Molecular basis of Diamond Blackfan anemia: structure and function analysis of RPS19 Nucleic Acids Res., September 27, 2007; 35(17): 5913 - 5921. [Abstract] [Full Text] [PDF]
|
|