scholarly journals The Genetic Landscape of Diamond-Blackfan Anemia

2018 ◽  
Author(s):  
Jacob C. Ulirsch ◽  
Jeffrey M. Verboon ◽  
Shideh Kazerounian ◽  
Michael H. Guo ◽  
Daniel Yuan ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Bone Marrow Failure ◽  
Loss Of Function ◽  
Diamond Blackfan Anemia ◽  
Rare Mutations ◽  
New Genes ◽  
Whole Exome ◽  
Genes Encoding ◽  
Causal Genes ◽  
Genetic Landscape

ABSTRACTDiamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 1 in 100,000 to 200,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this genetically heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole exome sequencing (WES). Overall, we identified rare and predicted damaging mutations in likely causal genes for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and in one of 19 previously reported genes encoding for a diverse set of ribosomal proteins (RPs). Using WES exon coverage estimates, we were able to identify and validate 31 deletions in DBA associated genes. We also observed an enrichment for extended splice site mutations and validated the diverse effects of these mutations using RNA sequencing in patientderived cell lines. Leveraging the size of our cohort, we observed several robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. In addition to comprehensively identifying mutations in known genes, we further identified rare mutations in 7 previously unreported RP genes that may cause DBA. We also identified several distinct disorders that appear to phenocopy DBA, including 9 individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain > 5% of DBA cases. Overall, this comprehensive report should not only inform clinical practice for DBA patients, but also the design and analysis of future rare variant studies for heterogeneous Mendelian disorders.

scholarly journals A new murine Rpl5(uL18) mutation provides a unique model of variably penetrant Diamond Blackfan Anemia

2021 ◽  
Author(s):  
Lei Yu ◽  
Philippe Lemay ◽  
Alexander V Ludlow ◽  
Marie-Claude Guyot ◽  
Morgan Alexander Jones ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Septal Defect ◽  
Macrocytic Anemia ◽  
Diamond Blackfan Anemia ◽  
Disease States ◽  
Whole Exome ◽  
Skeletal Defects ◽  
Genes Encoding ◽  
Erythroid Maturation ◽  
Variable Penetrance

Ribosome dysfunction is implicated in multiple abnormal developmental and disease states in humans. Heterozygous germline mutations in genes encoding ribosomal proteins (RPs) are found in the majority of individuals with Diamond Blackfan anemia (DBA) while somatic mutations have been implicated in a variety of cancers and other disorders. Ribosomal protein-deficient animal models show variable phenotypes and penetrance, similar to human DBA patients. Here we characterized a novel ENU mouse mutant (Skax23m1Jus) with growth and skeletal defects, cardiac malformations and increased mortality. Following genetic mapping and whole exome sequencing, we identified an intronic Rpl5 mutation, which segregated with all affected mice. This mutation was associated with decreased ribosome generation, consistent with Rpl5 haploinsufficiency. Rpl5Skax23-Jus/+ mutant animals had a profound delay in erythroid maturation and increased mortality at embryonic day E12.5, which improved by E14.5. Surviving mutant animals had a macrocytic anemia at birth as well as evidence of ventricular septal defect (VSD). Surviving adult and aged mice exhibited no hematopoietic defect or VSD. We propose that this novel Rpl5Skax23-Jus mutant mouse will be useful to study the factors influencing the variable penetrance that is observed in DBA.

scholarly journals A new murine Rpl5 (uL18) mutation provides a unique model of variably penetrant Diamond Blackfan Anemia

2021 ◽  
Author(s):  
Lei Yu ◽  
Philippe Lemay ◽  
Alexander Ludlow ◽  
Marie-Claude Guyot ◽  
Morgan Jones ◽  
...  
Keyword(s):  
Animal Models ◽  
Ribosomal Proteins ◽  
Macrocytic Anemia ◽  
Diamond Blackfan Anemia ◽  
Disease States ◽  
Whole Exome ◽  
Skeletal Defects ◽  
Genes Encoding ◽  
Erythroid Maturation ◽  
Variable Penetrance

AbstractRibosome dysfunction is implicated in multiple abnormal developmental and disease states in humans. Heterozygous germline mutations in genes encoding ribosomal proteins (RPs) are found in the majority of individuals with Diamond Blackfan anemia (DBA) while somatic mutations have been implicated in a variety of cancers and other disorders. Ribosomal protein-deficient animal models show variable phenotypes and penetrance, similar to human DBA patients. The spontaneous anemia remission observed in some DBA patients occurs via unknown mechanism(s) and has not been previously described in animal models. Here we characterized a novel ENU mouse mutant (Skax23m1Jus) with growth and skeletal defects, cardiac malformations and increased mortality. Following genetic mapping and whole exome sequencing, we identified an intronic Rpl5 mutation, which segregated with all affected mice. This mutation was associated with decreased ribosome generation, consistent with Rpl5 haploinsufficiency. Rpl5Skax23-Jus mutant animals had a profound delay in erythroid maturation and increased mortality at embryonic day E12.5, which improved by E14.5. Surviving mutant animals had a macrocytic anemia at birth as well as evidence of ventricular septal defect (VSD). Surviving adult and aged mice exhibited no hematopoietic defect or VSD. We propose that this novel Rpl5Skax23-Jus mutant mouse will be useful to study the factors influencing the variable penetrance and anemia remission that are observed in DBA.

Dietary L-leucine improves the anemia in a mouse model for Diamond-Blackfan anemia

Blood ◽  
2012 ◽  
Vol 120 (11) ◽  
pp. 2225-2228 ◽  
Author(s):  
Pekka Jaako ◽  
Shubhranshu Debnath ◽  
Karin Olsson ◽  
David Bryder ◽  
Johan Flygare ◽  
...  
Keyword(s):  
Mouse Model ◽  
Ribosomal Proteins ◽  
Therapeutic Agent ◽  
Hemoglobin Concentration ◽  
Response To Treatment ◽  
Diamond Blackfan Anemia ◽  
Genes Encoding ◽  
Marrow Cellularity ◽  
Deficient Mice

Abstract Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Recently, a case study reported a patient who became transfusion-independent in response to treatment with the amino acid L-leucine. Therefore, we have validated the therapeutic effect of L-leucine using our recently generated mouse model for RPS19-deficient DBA. Administration of L-leucine significantly improved the anemia in Rps19-deficient mice (19% improvement in hemoglobin concentration; 18% increase in the number of erythrocytes), increased the bone marrow cellularity, and alleviated stress hematopoiesis. Furthermore, the therapeutic response to L-leucine appeared specific for Rps19-deficient hematopoiesis and was associated with down-regulation of p53 activity. Our study supports the rationale for clinical trials of L-leucine as a therapeutic agent for DBA.

Beneficial Effects of Nucleoside Treatment in Zebrafish Models of Diamond Blackfan Anemia Deficient in Ribosomal Proteins L11 or S19,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3439-3439
Author(s):  
Nadia Danilova ◽  
Kathleen M Sakamoto ◽  
Shuo Lin
Keyword(s):  
Ribosomal Protein ◽  
Ribosomal Proteins ◽  
Research Funding ◽  
Bone Marrow Failure ◽  
Beneficial Effects ◽  
Diamond Blackfan Anemia ◽  
Positive Effects ◽  
Network Activation ◽  
Increased Risk ◽  
Dependent Signal

Abstract Abstract 3439 Deficiency of ribosomal protein (RPs) is associated with Diamond Blackfan Anemia, (DBA) a congenital syndrome with bone marrow failure and variable malformations. Recent studies of ours and other labs established p53 network activation as a major contributor to DBA. Therefore, modulation of p53-dependent pathways emerges as a most promising approach to DBA treatment. Direct suppression of 53 may, however, lead to increased risk of malignant transformation. Search for more physiological modulators of p53 pathways is therefore warranted. p53 has been shown both to respond to metabolic alterations and to change metabolism. Specifically, nutrients can influence p53 status through mTOR and other pathways. Recently, Ortega et al reported that treatment of Caco-2 cells with exogenous nucleosides modulated expression and activity of many transcription factors including p53 (J Nutr Biochem, 22:595, 2011). We applied treatment with exogenous nucleosides to RP-deficient zebrafish and found positive effects. As a DBA model, we use zebrafish mutant for ribosomal protein RPL11; we also employ morpholino nucleotides to create deficiency of various ribosomal proteins including RPS19. Treatment of both models resulted in inhibition of p53-dependent pathways. Specifically, expression of genes associated with cell cycle arrest such as p21 and p53 targets inducing apoptosis such as puma, was decreased by nucleoside treatment. We hypothesize that nucleoside treatment affects p53 by modulating the activity of mTOR and MEK/Erk pathways. Previously, Gu et al. showed that nucleotide depletion strongly inhibited mTOR and activated MEK/Erk. We also study how nucleoside treatment influences other stress-response pathways and affects interaction of p53 and mTOR pathways. Our data indicate that nucleosides may be effective in modulation of p53-dependent signal transduction pathways and suggest their usefulness for treatment of p53-associated disorders. Disclosures: Sakamoto: Abbott: Research Funding; Genentech: Research Funding.

scholarly journals Acquired ribosomopathies in leukemia and solid tumors

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 716-719 ◽  
Author(s):  
Adrianna Vlachos
Keyword(s):  
Bone Marrow ◽  
Ribosomal Protein ◽  
Solid Tumors ◽  
Ribosomal Proteins ◽  
Bone Marrow Failure ◽  
Ribosomal Protein Gene ◽  
Small Subunit ◽  
Gene Encoding ◽  
Bone Marrow Failure Syndrome ◽  
Diamond Blackfan Anemia

AbstractA mutation in the gene encoding the small subunit-associated ribosomal protein RPS19, leading to RPS19 haploinsufficiency, is one of the ribosomal protein gene defects responsible for the rare inherited bone marrow failure syndrome Diamond Blackfan anemia (DBA). Additional inherited and acquired defects in ribosomal proteins (RPs) continue to be identified and are the basis for a new class of diseases called the ribosomopathies. Acquired RPS14 haploinsufficiency has been found to be causative of the bone marrow failure found in 5q– myelodysplastic syndromes. Both under- and overexpression of RPs have also been implicated in several malignancies. This review will describe the somatic ribosomopathies that have been found to be associated with a variety of solid tumors as well as leukemia and will review cancers in which over- or underexpression of these proteins seem to be associated with outcome.

Yeast Models of Diamond Blackfan Anemia and Shwachman Diamond Syndrome Differ in Their Effect on the Synthesis and Function of Ribosomal Subunits.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2044-2044
Author(s):  
Steven R Ellis ◽  
Joseph B. Moore ◽  
Johnson M. Liu ◽  
Robert J. Arceci ◽  
Jason E. Farrar
Keyword(s):  
Structural Component ◽  
Ribosomal Proteins ◽  
Molecular Mechanisms ◽  
Bone Marrow Failure ◽  
Disease Models ◽  
Clinical Phenotypes ◽  
Diamond Blackfan Anemia ◽  
Nucleolar Stress ◽  
Shwachman Diamond Syndrome ◽  
And Function

Abstract Nucleolar stress is a frequently invoked mechanism used to describe the pro-apoptotic phenotype of cells affected in human diseases linked to abnormalities of the ribosome. However, the diversity of clinical phenotypes observed in these diseases suggests that there may be different types of nucleolar and/or translational stress that stimulate cell death pathways by alternative mechanisms. We have studied yeast models of Diamond Blackfan anemia (DBA) and Shwachman Diamond syndrome (SDS), two inherited bone marrow failure syndromes linked to defects in ribosome synthesis and/or function, to determine potential underlying molecular mechanisms that distinguish these disease models. To date, all genes identified in DBA encode ribosomal proteins. In contrast, SBDS, the gene affected in SDS encodes a protein that associates with 60S subunits, but is not considered a structural component of the ribosome. We have analyzed the translational capacity of cells harboring mutations in RPL33A and SDO1, yeast orthologs of genes affected in DBA and SDS, respectively. Polysome profiles from cells depleted of Rpl33A have a decrease in the amount of free 60S subunits and the presence of half-mer polysomes, as expected for an essential structural component of the 60S subunit. Polysome profiles from cells depleted of Sdo1 also had half-mer polysomes, but in this case there were significant amounts of free 60S subunits evident. Analysis of the intracellular distribution of 60S subunits by fluorescence microscopy revealed significant differences between the two disease models. In the DBA model, there was no evidence of accumulation of incompletely assembled subunits in the nucleolus indicating that rapid degradation. In contrast, in the SDS model there was significant accumulation of 60S subunits in the nucleoplasm. Thus, the two disease models interfere with the biogenesis of 60S subunits through distinct mechanisms. To determine if these mechanistic differences influence protein synthesis, we analyzed the patterns of proteins synthesized in these two disease models. We found that the expression of the 20S replicon was induced in both models, a sign of general translational stress. However, the two models also showed distinct differences in the synthesis of certain proteins. Thus, the mechanisms by which reductions of Rpl33A or Sdo1 influence levels of functional 60S subunits have differential effects on the patterns of proteins synthesized within cells Together these data indicate that the ribosome-based diseases may result from a composite of effects that include both nucleolar stress mechanisms and changes in translational output. The distinct clinical phenotypes observed in these disorders may result from differences in the relative contributions of either of these two mechanisms.

Ribosome Dysfunction and Ineffective Hematopoiesis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-11-SCI-11
Author(s):  
Benjamin L. Ebert
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Bone Marrow Failure ◽  
Ribosomal Genes ◽  
Limb Bud ◽  
Refractory Anemia ◽  
Diamond Blackfan Anemia ◽  
Rare Congenital Disorder ◽  
Human Disorders ◽  
And Function

Abstract Abstract SCI-11 The 5q- syndrome and Diamond Blackfan Anemia are related on a molecular level by ribosome dysfunction. The 5q- syndrome is a distinct subtype of myelodysplastic syndrome (MDS) associated with isolated, interstitial deletions of the long arm of Chromosome 5. Diamond Blackfan Anemia is a rare congenital disorder associated with bone marrow failure, craniofacial abnormalities, and limb bud defects. The hematologic phenotype of both diseases includes a severe refractory anemia, macrocytosis, and a deficiency of erythroid precursors. Recent evidence indicates that this erythroid defect is caused by RPS14 deletion in the 5q- syndrome, and by mutation of RPS19 or other ribosomal genes in at least 50% of patients with Diamond Blackfan Anemia. In both diseases, deletion or mutation of one allele of a ribosomal protein leads to defects in pre-rRNA processing and defective production of mature ribosomes. In murine and zebrafish models, haploinsufficiency for ribosomal genes phenocopies the erythroid failure characteristic of the human disorders. While the mechanistic consequences of ribosomal dysfunction have not been fully elucidated, the p53 pathway appears to play a central role. MDM2, an E3 ubiquitin ligase that promotes the degradation of p53, binds to several ribosomal proteins including RPL11. Deficiency of RPS6, and perhaps other ribosomal proteins, causes an accumulation of free RPL11, that binds to MDM2, preventing MDM2 from interacting with p53, thereby leading to an accumulation of p53. Several other genes that are mutated in hematologic disorders are involved in ribosome biogenesis and function, including SBDS, mutated in Shwachman Diamond syndrome; DKC1, mutated in some cases of dyskaratosis congenita; and NPM1, mutated in acute myeloid leukemia and deleted in some cases of MDS. The manner in which each of these genes disrupt ribosome function and cause distinct clinical phenotypes is currently under investigation. Disclosures Ebert: GlaxoSmithKline: Research Funding.

scholarly journals An update on the pathogenesis and diagnosis of Diamond–Blackfan anemia

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1350 ◽  
Author(s):  
Lydie Da Costa ◽  
Anupama Narla ◽  
Narla Mohandas
Keyword(s):  
Genetic Testing ◽  
Congenital Malformations ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Macrocytic Anemia ◽  
Diamond Blackfan Anemia ◽  
Biological Features ◽  
Genes Encoding ◽  
History Of ◽  
Hypoplastic Anemia

Diamond–Blackfan anemia (DBA) is a rare congenital hypoplastic anemia characterized by a block in erythropoiesis at the progenitor stage, although the exact stage at which this occurs remains to be fully defined. DBA presents primarily during infancy with macrocytic anemia and reticulocytopenia with 50% of cases associated with a variety of congenital malformations. DBA is most frequently due to a sporadic mutation (55%) in genes encoding several different ribosomal proteins, although there are many cases where there is a family history of the disease with varying phenotypes. The erythroid tropism of the disease is still a matter of debate for a disease related to a defect in global ribosome biogenesis. Assessment of biological features in conjunction with genetic testing has increased the accuracy of the diagnosis of DBA. However, in certain cases, it continues to be difficult to firmly establish a diagnosis. This review will focus on the diagnosis of DBA along with a description of new advances in our understanding of the pathophysiology and treatment recommendations for DBA.

Diamond Blackfan Anemia

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 487-491 ◽  
Author(s):  
Sarah Ball
Keyword(s):  
Ribosomal Proteins ◽  
Leukemia Virus ◽  
Feline Leukemia Virus ◽  
Leucine Supplementation ◽  
Therapeutic Implications ◽  
Diamond Blackfan Anemia ◽  
Increased Risk ◽  
Genes Encoding ◽  
Risk Of Malignancy ◽  
Virus C

Abstract Mutations affecting genes encoding ribosomal proteins cause Diamond Blackfan anemia (DBA), a rare congenital syndrome associated with physical anomalies, short stature, red cell aplasia, and an increased risk of malignancy. p53 activation has been identified as a key component in the pathophysiology of DBA after cellular and molecular studies of knockdown cellular and animal models of DBA and other disorders affecting ribosomal assembly or function. Other potential mechanisms that warrant further investigation include impaired translation as the result of ribosomal insufficiency, which may be ameliorated by leucine supplementation, and alternative splicing leading to reduced expression of a cytoplasmic heme exporter, the human homolog of the receptor for feline leukemia virus C (FVLCR). However, the molecular basis for the characteristic steroid responsiveness of the erythroid failure in DBA remains unknown. This review explores the clinical and therapeutic implications of the current state of knowledge and delineates important but as-yet-unanswered questions.

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