Abstract:Diamond-Blackfan anemia (DBA), an inherited bone marrow failure syndrome characterized by anemia that usually presents before the first birthday or in early childhood, is associated with birth defects and an increased risk of cancer. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, in particular craniofacial, upper limb, heart, and urinary system defects that are present in approximately 30%-50% of patients. DBA has been… Show more
“…TSR2 interacts with RPS26, as indicated in genecard (www.genecards.org) and the UniProtKB database (www.uniprot.org). This is relevant because RPS26 is a known DBA causing gene [Doherty et al, 2010]. Furthermore, we identified pathogenic RPS26 mutations in Families 2 and 3.…”
Section: Discussionmentioning
confidence: 99%
“…Mutations in RPS26 account for about 6.4% of patients with DBA, and numerous mutations, including those affecting the start codon and others resulting in frame shifts, were reported by Doherty et al [2010]. Doherty et al [2010] mention cleft lip and cleft palate in one individual with a RPS26 mutation, however this information is absent in the accompanying table listing the patients'findings. Cleft palate in the context of cleft lip is typically considered etiologically distinct from isolated cleft palate or clefting seen in TCS.…”
Patients with physical findings suggestive of Treacher Collins syndrome (TCS) or mandibulofacial dystosis (MFD) and macrocytic anemia diagnostic of Diamond Blackfan anemia (DBA) have been reported. Disease causing genes have been identified for TCS and other MFDs. Mutations in several ribosomal protein genes and the transcription factor GATA1 result in DBA. However, no disease causing mutation had been identified in the reported patients with the combination of TCS/MFD and DBA phenotype, and we hypothesized that pathogenic mutations in a single gene could be identified using whole exome analysis. We studied probands from 6 unrelated families. Combining exome analysis and Sanger sequencing, we identified likely pathogenic mutations in 5/6 families. Two mutations in unrelated families were seen in RPS26, the known DBA10 gene. One variant was predicted to affect mRNA splicing, and the other to lead to protein truncation. In another family a likely pathogenic X-linked mutation affecting a highly conserved residue was found in TSR2, which encodes a direct binding partner of RPS26. De novo mutations affecting the RPS28 start codon were found in two unrelated probands, identifying RPS28 as a novel disease gene. We conclude that the phenotype combining features of TCS with DBA is genetically heterogeneous. Each of the pathogenic variants identified is predicted to impede ribosome biogenesis, which in turn could result in altered cell growth and proliferation, causing abnormal embryologic development, defective erythropoiesis and reduced growth. The phenotype combining TCS/MFD and DBA is highly variable, overlaps with DBA and lies within the phenotypic spectrum of ribosomopathies.
“…TSR2 interacts with RPS26, as indicated in genecard (www.genecards.org) and the UniProtKB database (www.uniprot.org). This is relevant because RPS26 is a known DBA causing gene [Doherty et al, 2010]. Furthermore, we identified pathogenic RPS26 mutations in Families 2 and 3.…”
Section: Discussionmentioning
confidence: 99%
“…Mutations in RPS26 account for about 6.4% of patients with DBA, and numerous mutations, including those affecting the start codon and others resulting in frame shifts, were reported by Doherty et al [2010]. Doherty et al [2010] mention cleft lip and cleft palate in one individual with a RPS26 mutation, however this information is absent in the accompanying table listing the patients'findings. Cleft palate in the context of cleft lip is typically considered etiologically distinct from isolated cleft palate or clefting seen in TCS.…”
Patients with physical findings suggestive of Treacher Collins syndrome (TCS) or mandibulofacial dystosis (MFD) and macrocytic anemia diagnostic of Diamond Blackfan anemia (DBA) have been reported. Disease causing genes have been identified for TCS and other MFDs. Mutations in several ribosomal protein genes and the transcription factor GATA1 result in DBA. However, no disease causing mutation had been identified in the reported patients with the combination of TCS/MFD and DBA phenotype, and we hypothesized that pathogenic mutations in a single gene could be identified using whole exome analysis. We studied probands from 6 unrelated families. Combining exome analysis and Sanger sequencing, we identified likely pathogenic mutations in 5/6 families. Two mutations in unrelated families were seen in RPS26, the known DBA10 gene. One variant was predicted to affect mRNA splicing, and the other to lead to protein truncation. In another family a likely pathogenic X-linked mutation affecting a highly conserved residue was found in TSR2, which encodes a direct binding partner of RPS26. De novo mutations affecting the RPS28 start codon were found in two unrelated probands, identifying RPS28 as a novel disease gene. We conclude that the phenotype combining features of TCS with DBA is genetically heterogeneous. Each of the pathogenic variants identified is predicted to impede ribosome biogenesis, which in turn could result in altered cell growth and proliferation, causing abnormal embryologic development, defective erythropoiesis and reduced growth. The phenotype combining TCS/MFD and DBA is highly variable, overlaps with DBA and lies within the phenotypic spectrum of ribosomopathies.
“…Finally, although initial endonucleolytic cleavage of the ITS1 at site A 2 in yeast is dependent on elimination of the ETS1 by cleavage at sites A 0 and A 1 , the relative order of the cleavage of the 5′-ETS (ETS1) and the ITS1 is flexible in vertebrate cells, leading to several maturation pathways defined by specific processing intermediates (Figure 1) (15,16). Noticeably, mutations in DBA affect ITS1 processing in a large proportion of cases, especially after mutation of the small ribosomal subunit protein genes RPS19 (17–19), RPS26 (20), RPS10 (20) and RPS17 (21), but also of the large subunit protein gene RPL26 (22). Figure 1.Processing of the pre-ribosomal RNAs.…”
Defects in ribosome biogenesis trigger stress response pathways, which perturb cell proliferation and differentiation in several genetic diseases. In Diamond–Blackfan anemia (DBA), a congenital erythroblastopenia, mutations in ribosomal protein genes often interfere with the processing of the internal transcribed spacer 1 (ITS1), the mechanism of which remains elusive in human cells. Using loss-of-function experiments and extensive RNA analysis, we have defined the precise position of the endonucleolytic cleavage E in the ITS1, which generates the 18S-E intermediate, the last precursor to the 18S rRNA. Unexpectedly, this cleavage is followed by 3′–5′ exonucleolytic trimming of the 18S-E precursor during nuclear export of the pre-40S particle, which sets a new mechanism for 18S rRNA formation clearly different from that established in yeast. In addition, cleavage at site E is also followed by 5′–3′ exonucleolytic trimming of the ITS1 by exonuclease XRN2. Perturbation of this step on knockdown of the large subunit ribosomal protein RPL26, which was recently associated to DBA, reveals the putative role of a highly conserved cis-acting sequence in ITS1 processing. These data cast new light on the original mechanism of ITS1 elimination in human cells and provide a mechanistic framework to further study the interplay of DBA-linked ribosomal proteins in this process.
“…Pathogenic mutations in RPS19[3], RPS24[4], RPS17[5], RPL35A[6], RPL5, RPL11, RPS7[7], RPS10, and RPS26[8] have been identified in patients. Patients are always heterozygous for the mutations and maintain one copy of the unmutated ribosomal protein.…”
Disruption of ribosomal proteins is associated with hematopoietic phenotypes in cell culture and animal models. Mutations in ribosomal proteins are seen in patients with Diamond Blackfan anemia (DBA), a rare congenital disease characterized by red cell aplasia and distinctive craniofacial anomalies. A zebrafish screen uncovered decreased hematopoietic stem cells (HSCs) in embryos with mutations in ribosomal protein rps29. Here, we determined that rps29-/- embryos also have red blood cell defects and increased apoptosis in the head. As the p53 pathway has been shown to play a role in other ribosomal protein mutants, we studied the genetic relationship of rps29 and p53. Transcriptional profiling revealed that genes up-regulated in the rps29 mutant are enriched for genes up-regulated by p53 after irradiation. p53 mutation near completely rescues the rps29 morphological and hematopoietic phenotypes, demonstrating that p53 mediates the effects of rps29 knockdown. We also identified neuronal gene orthopedia protein a (otpa) as one whose expression correlates with rps29 expression, suggesting that levels of expression of some genes are dependent on rps29 levels. Together, our studies demonstrate a role of p53 in mediating the cellular defects associated with rps29 and establish a role for rps29 and p53 in HSCs and red blood cell development.
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