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 similar to 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, (111) 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.

Angelini, M., Cannata, S., Mercaldo, V., Gibello, L., Santoro, C., Dianzani, I., et al. (2007). Missense mutations associated with Diamond-Blackfan anemia affect the assembly of ribosomal protein S19 into the ribosome. HUMAN MOLECULAR GENETICS, 16(14), 1720-1727 [10.1093/hmg/ddm120].

Missense mutations associated with Diamond-Blackfan anemia affect the assembly of ribosomal protein S19 into the ribosome

CANNATA, STEFANO;LORENI, FABRIZIO
2007-01-01

Abstract

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 similar to 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, (111) 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.
2007
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/11 - BIOLOGIA MOLECOLARE
English
Con Impact Factor ISI
complementary DNA; messenger RNA; protein S19; ribosome protein; RNA 18S; article; Blackfan Diamond anemia; cellular distribution; controlled study; gene expression; gene insertion; genetic association; genetic transfection; human; human cell; missense mutation; nucleolus; pathophysiology; phenotype; priority journal; protein assembly; protein function; protein localization; protein stability; stop codon; Anemia, Diamond-Blackfan; Cell Line; Centrifugation, Density Gradient; DNA, Complementary; Gene Expression Regulation; Hela Cells; Humans; Models, Biological; Mutation; Mutation, Missense; Proteins; Ribosomal Proteins; Ribosomes; Subcellular Fractions; Sucrose
Angelini, M., Cannata, S., Mercaldo, V., Gibello, L., Santoro, C., Dianzani, I., et al. (2007). Missense mutations associated with Diamond-Blackfan anemia affect the assembly of ribosomal protein S19 into the ribosome. HUMAN MOLECULAR GENETICS, 16(14), 1720-1727 [10.1093/hmg/ddm120].
Angelini, M; Cannata, S; Mercaldo, V; Gibello, L; Santoro, C; Dianzani, I; Loreni, F
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/26164
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