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Ribosomal protein S19 binds to its own mRNA with reduced affinity in Diamond-Blackfan anemia.

ABSTRACT: Heterozygous mutations in the ribosomal protein S19 (RPS19) gene are associated with Diamond-Blackfan anemia (DBA). The mechanism by which RPS19 mediates anemia are still unclear, as well as the regulation of RPS19 expression. We show herein that RPS19 binds specifically to the 5' untranslated region of its own mRNA with an equilibrium binding constant (K(D)) of 4.1+/-1.9 nM. We investigated the mRNA binding properties of two mutant RPS19 proteins (W52R and R62W) identified in DBA patients. We observed a significant increase in K(D) for both proteins (16.1+/-2.1 and 14.5+/-4.9 nM, respectively), indicating a reduced RNA binding capability (p<0.05). We suggest that the binding of RPS19 to its mRNA has a regulatory function and hypothesize that the weaker RNA binding of mutant rRPS19 may have implications for the pathophysiological mechanisms in DBA.

SUBMITTER: Schuster J

PROVIDER: S-EPMC2878864 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Ribosomal protein S19 binds to its own mRNA with reduced affinity in Diamond-Blackfan anemia.

Schuster Jens J Fröjmark Anne-Sophie AS Nilsson Per P Badhai Jitendra J Virtanen Anders A Dahl Niklas N

Blood cells, molecules & diseases 20100414 1

Heterozygous mutations in the ribosomal protein S19 (RPS19) gene are associated with Diamond-Blackfan anemia (DBA). The mechanism by which RPS19 mediates anemia are still unclear, as well as the regulation of RPS19 expression. We show herein that RPS19 binds specifically to the 5' untranslated region of its own mRNA with an equilibrium binding constant (K(D)) of 4.1+/-1.9 nM. We investigated the mRNA binding properties of two mutant RPS19 proteins (W52R and R62W) identified in DBA patients. We o ...[more]

PMID: 20395159

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Ribosomal protein S19 and S24 insufficiency cause distinct cell cycle defects in Diamond-Blackfan anemia.

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Ribosomal protein gene deletions in Diamond-Blackfan anemia.

Project description:Diamond-Blackfan anemia (DBA) is a congenital BM failure syndrome characterized by hypoproliferative anemia, associated physical abnormalities, and a predisposition to cancer. Perturbations of the ribosome appear to be critically important in DBA; alterations in 9 different ribosomal protein genes have been identified in multiple unrelated families, along with rarer abnormalities of additional ribosomal proteins. However, at present, only 50% to 60% of patients have an identifiable genetic lesion by ribosomal protein gene sequencing. Using genome-wide single-nucleotide polymorphism array to evaluate for regions of recurrent copy variation, we identified deletions at known DBA-related ribosomal protein gene loci in 17% (9 of 51) of patients without an identifiable mutation, including RPS19, RPS17, RPS26, and RPL35A. No recurrent regions of copy variation at novel loci were identified. Because RPS17 is a duplicated gene with 4 copies in a diploid genome, we demonstrate haploinsufficient RPS17 expression and a small subunit ribosomal RNA processing abnormality in patients harboring RPS17 deletions. Finally, we report the novel identification of variable mosaic loss involving known DBA gene regions in 3 patients from 2 kindreds. These data suggest that ribosomal protein gene deletion is more common than previously suspected and should be considered a component of the initial genetic evaluation in cases of suspected DBA.

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Ribosomal Protein Gene Deletions in Diamond Blackfan Anemia

2012-01-15 | GSE31575 | GEO

Ribosomal Protein Gene Deletions in Diamond Blackfan Anemia

Project description:Diamond Blackfan anemia is a congenital bone marrow failure syndrome characterized by hypoproliferative anemia, often with associated physical abnormalities. Perturbations of the ribosome appear critically important to the development of DBA, as alterations in 9 different ribosomal protein genes have been identified in multiple unrelated families, along with rarer abnormalities of additional ribosomal proteins. However, presently only 50-60% of patients have an identifiable genetic lesion by ribosomal protein gene sequencing. Using genome-wide SNP array to evaluate for regions of recurrent copy variation, we identified deletions at known DBA-related ribosomal protein gene loci in 17% (9/51) of patients without an identifiable mutation, including RPS19, RPS17, RPS26, and RPL35A [Illumina platforms] A total of 68 samples were analyzed on Illumina Omni1_Quad or Illumina OmniExpress Genotyping bead arrays; 51 affected probands, 1 affected sibling, 1 unaffected sibling, and 15 parents. [NimbleGen platform] 5 samples where a deletion was identified by SNP array and one sample where no deletion was identified were run on Nimblegen Human CGH 3x720K Whole-Genome Exon-Focused arrays for confirmation.

2012-01-15 | E-GEOD-31575 | biostudies-arrayexpress

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Ribosomal protein mutations in Korean patients with Diamond-Blackfan anemia.

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Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia.

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Diamond-Blackfan anemia.

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