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Defective ribosomal protein gene expression alters transcription, translation, apoptosis, and oncogenic pathways in Diamond-Blackfan anemia.

ABSTRACT: Transcriptome profile of highly purified multipotential (P), erythroid (E), and myeloid (M) bone marrow progenitors from three RPS19 mutated Diamond-Blackfan anemia and six control human subjects. Two group comparison of sex and age matched subjects. Bone marrow progenitors, gene expression profiling, Diamond-Blackfan anemia, RPS19

ORGANISM(S): Homo sapiens

SUBMITTER: Alvin Kho

PROVIDER: E-GEOD-41599 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Defective ribosomal protein gene expression alters transcription, translation, apoptosis, and oncogenic pathways in Diamond-Blackfan anemia.

Gazda Hanna T HT Kho Alvin T AT Sanoudou Despina D Zaucha Jan M JM Kohane Isaac S IS Sieff Colin A CA Beggs Alan H AH

Stem cells (Dayton, Ohio) 20060601 9

Diamond-Blackfan anemia (DBA) is a broad developmental disease characterized by anemia, bone marrow (BM) erythroblastopenia, and an increased incidence of malignancy. Mutations in ribosomal protein gene S19 (RPS19) are found in approximately 25% of DBA patients; however, the role of RPS19 in the pathogenesis of DBA remains unknown. Using global gene expression analysis, we compared highly purified multipotential, erythroid, and myeloid BM progenitors from RPS19 mutated and control individuals. W ...[more]

PMID: 16741228

Similar Datasets

Defective ribosomal protein gene expression alters transcription, translation, apoptosis, and oncogenic pathways in Diamond-Blackfan anemia.

Project description:Transcriptome profile of highly purified multipotential (P), erythroid (E), and myeloid (M) bone marrow progenitors from three RPS19 mutated Diamond-Blackfan anemia and six control human subjects.

2012-10-16 | GSE41599 | GEO

Gene expression analysis from erythroid progenitors of patients with Diamond-Blackfan anemia

Project description:Gene expression analysis from erythroid progenitors (CD34+/CD71(high)/CD45- mononuclear cells from the bone marrow) of patients with Diamond-Blackfan anemia (due to RPS19 mutations) and control individuals.

2014-02-28 | GSE41817 | GEO

Gene expression analysis from erythroid progenitors of patients with Diamond-Blackfan anemia

2014-02-28 | E-GEOD-41817 | biostudies-arrayexpress

Mechanism of action of RPS19R62W mutation in Diamond-Blackfan Anemia (DBA)

Project description:RPS19 mutations are the most common cause of the human disorder Diamond Blackfan Anemia. The R62W mutation was hypothesized to act in a dominant negative fashion and mice expressing RPS19R62W have many of the characteristics of Diamond Blackfan Anemia. Diamond-Blackfan Anemia (DBA), is an inherited erythroblastopenia associated with mutations in at least 8 different ribosomal protein genes. Mutations in the gene encoding Ribosomal Protein S19 (RPS19) have been identified in ~25% of DBA families. Most of these mutations disrupt either the translation or stability of the RPS19 protein and are predicted to cause DBA by haploinsufficiency. However, approximately ~30% of RPS19 mutations are missense mutations that do not alter the stability of the RPS19 protein and are hypothesized to act by a dominant negative mechanism. To formally test this hypothesis, we generated a transgenic mouse model expressing an RPS19 mutation in which an Arginine residue is replaced with a Tryptophan residue at codon 62 (RPS19R62W). Constitutive expression of RPS19R62W in developing mice was lethal. Conditional expression of RPS19R62W resulted in growth retardation, a mild anemia with reduced numbers of erythroid progenitors and significant inhibition of terminal erythroid maturation, similar to DBA. RNA profiling demonstrated over 700 dysregulated genes belonging to the same pathways that are disrupted in RNA profiles of DBA patient cells. The samples compared are RNA extracted from CD71 positive erythroblasts sorted from the bone marrow of wild type mice and mice expressing a mutant RPS19 (RPS19R62W) transgene

2011-06-29 | E-GEOD-22645 | biostudies-arrayexpress

Mechanism of action of RPS19R62W mutation in Diamond-Blackfan Anemia (DBA)

2011-06-29 | GSE22645 | GEO

RPS19 binding with and without Diamond-Blackfan anemia variants

Project description:We found that endogenously expressed RPS19 binds evolutionarily constrained intronic elements. By assessing overexpression of WT RPS19 and RPS19 harboring the most common Diamond-Blackfan anemia missense mutations, we confirmed that disease-relevant mutations alter RPS19 binding preferences in human cells.

2023-02-14 | GSE224998 | GEO

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

Partial loss of Rpl11 in adult mice recapitulates Diamond-Blackfan anemia (DBA) and promotes lymphomagenesis

Project description:Diamond-Blackfan anemia (DBA) is characterized by anemia and cancer susceptibility, and is caused by mutations in ribosomal genes, including Rpl11. Here, we report that Rpl11-heterozygous embryos are not viable, and homozygous deletion of Rpl11 in adult mice results in death within a few weeks, accompanied by bone marrow aplasia and intestinal atrophy. Importantly, deletion of a single Rpl11 allele in adult mice results in anemia associated to decreased erythroid progenitors and defective erythroid maturation. These phenotypes are also present in mice transplanted with inducible heterozygous Rpl11 bone marrow, indicating a cell-autonomous role of RPL11 in erythropoiesis. Additionally, fibroblasts lacking one or both Rpl11 alleles show defective p53 activation upon ribosomal stress or DNA damage. Furthermore, fibroblasts and hematopoietic tissues from heterozygous Rpl11 mice present higher basal cMYC levels. Accordingly, heterozygous Rpl11 mice are highly susceptible to radiation-induced lymphomagenesis. We conclude that Rpl11-deficient mice recapitulate DBA disorder, including cancer predisposition. RNAseq profiles of bone marrow hematopoietic progenitors cells from WT (Rpl11+/+:: Tg.UbC-CreERT2) and LOX (Rpl11+/lox::Tb.Ub-CreERT2) mice, n=4 independent animals per genotype

2015-09-01 | E-GEOD-72537 | biostudies-arrayexpress

5q- Myelodysplastic Syndrome Masquerading as Diamond Blackfan Anemia

2013-11-05 | GSE42570 | GEO