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1.
J Clin Invest ; 130: 3821-3826, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31211692

RESUMO

Shwachman-Diamond Syndrome (SDS) is a rare and clinically-heterogeneous bone marrow (BM) failure syndrome caused by mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. Although SDS was described over 50 years ago, the molecular pathogenesis is poorly understood due, in part, to the rarity and heterogeneity of the affected hematopoietic progenitors. To address this, we used single cell RNA sequencing to profile scant hematopoietic stem and progenitor cells from SDS patients. We generated a single cell map of early lineage commitment and found that SDS hematopoiesis was left-shifted with selective loss of granulocyte-monocyte progenitors. Transcriptional targets of transforming growth factor-beta (TGFß) were dysregulated in SDS hematopoietic stem cells and multipotent progenitors, but not in lineage-committed progenitors. TGFß inhibitors (AVID200 and SD208) increased hematopoietic colony formation of SDS patient BM. Finally, TGFß3 and other TGFß pathway members were elevated in SDS patient blood plasma. These data establish the TGFß pathway as a novel candidate biomarker and therapeutic target in SDS and translate insights from single cell biology into a potential therapy.

2.
JBJS Case Connect ; 9(2): e0376, 2019 Apr-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31085938

RESUMO

CASE: We report on a patient with heterozygous prothrombin G20210A mutation (PTM) and a history of venous thromboembolism (VTE) after knee arthroscopy, who was undergoing hip arthroscopy. This common mutation has an overall prevalence of 2.0% and results in a 280% to 420% likelihood of thrombosis compared to patients without the mutation. CONCLUSIONS: Hip arthroscopy is associated with a low risk of VTE with currently no guidelines for thromboprophylaxis. Patients should be managed in relation to their risk factors utilizing a collaborative, individualized approach. Treatment with short-term low-molecular-weight heparin resulted in no thromboembolism at 18-month follow-up for this patient with PTM.

4.
Am J Hum Genet ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30503522

RESUMO

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and located in 1 of 19 previously reported ribosomal protein (RP)-encoding genes. Using exon coverage estimates, we identified and validated 31 deletions in RP genes. We also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in cell lines obtained from individuals with DBA. Leveraging the size of our cohort, we observed robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. We further identified rare mutations in seven previously unreported RP genes that may cause DBA, as well as several distinct disorders that appear to phenocopy DBA, including nine 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-affected case subjects. Overall, this report should inform not only clinical practice for DBA-affected individuals, but also the design and analysis of rare variant studies for heterogeneous Mendelian disorders.

5.
Haematologica ; 2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-30026338

RESUMO

YARS2 variants have previously been described in patients with myopathy, lactic acidosis and sideroblastic anemia 2 (MLASA2). YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase, which is responsible for conjugating tyrosine to its cognate mt-tRNA for mitochondrial protein synthesis. Here we describe 14 individuals from 11 families presenting with sideroblastic anemia and with YARS2 variants that we identified using a sideroblastic anemia gene panel or exome sequencing. The phenotype of these patients ranged from MLASA to isolated congenital sideroblastic anemia. As in previous cases, inter- and intra-familial phenotypic variability was observed, however this report includes the first cases with isolated sideroblastic anemia and patients with biallelic YARS2 variants that have no clinically ascertainable phenotype. We identified ten novel YARS2 variants and three previously reported variants. In vitro amino-acylation assays of three five novel missense variants showed they that three had less effect on the catalytic activity of YARS2 than the most commonly reported variant, p.(Phe52Leu), associated with MLASA2, which may explain the milder phenotypes in patients with these variants. However, the other two missense variants had a more severe effect on YARS2 catalytic efficiency. Several patients carried the common YARS2 c.572 G>T, p.(Gly191Val) variant (minor allele frequency = 0.1259) in trans with a rare deleterious YARS2 variant. We have previously shown that the p.(Gly191Val) variant reduces YARS2 catalytic activity. Consequently, we suggest that biallelic YARS2 variants, including severe loss-of-function alleles in trans of the common p.(Gly191Val) variant, should be considered as a cause of isolated congenital sideroblastic anemia, as well as the MLASA syndromic phenotype.

6.
Hematol Oncol Clin North Am ; 32(4): 569-580, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30047411

RESUMO

Acquired aplastic anemia and inherited bone marrow failure syndromes both present with pancytopenia and must be distinguished because they have differences in treatment decisions and continued monitoring requirements. Advances in the genetic interrogation of patient samples have led to identification of inherited germline diseases and appreciation that patients with inherited bone marrow failure disorders may be normal in appearance with few expected clinical clues. Somatic mutations in aplastic anemia may have prognostic value. Hematopoietic stem cells from inherited marrow failure diseases can correct the proliferative defect and may develop further somatic mutations that progress to myelodysplastic syndrome or acute myeloid leukemia.

7.
Hematol Oncol Clin North Am ; 32(4): 701-712, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30047421

RESUMO

Diamond-Blackfan anemia (DBA) is a severe congenital hypoplastic anemia caused by mutation in a ribosomal protein gene. Major clinical issues concern the optimal management of patients resistant to steroids, the first-line therapy. Hematopoietic stem cell transplantation is indicated in young patients with an HLA-matched unaffected sibling donor, and recent results with matched unrelated donor transplants indicate that these patients also do well. When neither steroids nor a transplant is possible red cell transfusions are required, and iron loading is rapid in some DBA patients, so effective chelation is vital. Also discussed are novel treatments under investigation for DBA.

8.
Hematol Oncol Clin North Am ; 32(4): xiii-xiv, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30047424
9.
Sci Transl Med ; 9(376)2017 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-28179501

RESUMO

Diamond-Blackfan anemia (DBA) is a congenital disorder characterized by the failure of erythroid progenitor differentiation, severely curtailing red blood cell production. Because many DBA patients fail to respond to corticosteroid therapy, there is considerable need for therapeutics for this disorder. Identifying therapeutics for DBA requires circumventing the paucity of primary patient blood stem and progenitor cells. To this end, we adopted a reprogramming strategy to generate expandable hematopoietic progenitor cells from induced pluripotent stem cells (iPSCs) from DBA patients. Reprogrammed DBA progenitors recapitulate defects in erythroid differentiation, which were rescued by gene complementation. Unbiased chemical screens identified SMER28, a small-molecule inducer of autophagy, which enhanced erythropoiesis in a range of in vitro and in vivo models of DBA. SMER28 acted through autophagy factor ATG5 to stimulate erythropoiesis and up-regulate expression of globin genes. These findings present an unbiased drug screen for hematological disease using iPSCs and identify autophagy as a therapeutic pathway in DBA.


Assuntos
Anemia de Diamond-Blackfan/tratamento farmacológico , Descoberta de Drogas , Células-Tronco Hematopoéticas/metabolismo , Compostos Alílicos/farmacologia , Anemia de Diamond-Blackfan/patologia , Antígenos CD34/metabolismo , Autofagia/efeitos dos fármacos , Proteína 5 Relacionada à Autofagia/metabolismo , Diferenciação Celular/efeitos dos fármacos , Reprogramação Celular , Células Eritroides/efeitos dos fármacos , Células Eritroides/patologia , Eritropoese/efeitos dos fármacos , Teste de Complementação Genética , Globinas/metabolismo , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Quinazolinas/farmacologia
10.
Nat Med ; 20(7): 748-53, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24952648

RESUMO

Ribosomal protein haploinsufficiency occurs in diverse human diseases including Diamond-Blackfan anemia (DBA), congenital asplenia and T cell leukemia. Yet, how mutations in genes encoding ubiquitously expressed proteins such as these result in cell-type- and tissue-specific defects remains unknown. Here, we identify mutations in GATA1, encoding the critical hematopoietic transcription factor GATA-binding protein-1, that reduce levels of full-length GATA1 protein and cause DBA in rare instances. We show that ribosomal protein haploinsufficiency, the more common cause of DBA, can lead to decreased GATA1 mRNA translation, possibly resulting from a higher threshold for initiation of translation of this mRNA in comparison with other mRNAs. In primary hematopoietic cells from patients with mutations in RPS19, encoding ribosomal protein S19, the amplitude of a transcriptional signature of GATA1 target genes was globally and specifically reduced, indicating that the activity, but not the mRNA level, of GATA1 is decreased in patients with DBA associated with mutations affecting ribosomal proteins. Moreover, the defective hematopoiesis observed in patients with DBA associated with ribosomal protein haploinsufficiency could be partially overcome by increasing GATA1 protein levels. Our results provide a paradigm by which selective defects in translation due to mutations affecting ubiquitous ribosomal proteins can result in human disease.


Assuntos
Anemia de Diamond-Blackfan/genética , Fator de Transcrição GATA1/genética , Biossíntese de Proteínas , Humanos , Mutação , RNA Mensageiro/genética , Proteínas Ribossômicas/genética
11.
Hum Genet ; 132(11): 1265-74, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23812780

RESUMO

Diamond-Blackfan anemia (DBA) is an inherited red blood cell aplasia that usually presents during the first year of life. The main features of the disease are normochromic and macrocytic anemia, reticulocytopenia, and nearly absent erythroid progenitors in the bone marrow. The patients also present with growth retardation and craniofacial, upper limb, heart and urinary system congenital malformations in ~30-50 % of cases. The disease has been associated with point mutations and large deletions in ten ribosomal protein (RP) genes RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS10, RPS26, and RPL26 and GATA1 in about 60-65 % of patients. Here, we report a novel large deletion in RPL15, a gene not previously implicated to be causative in DBA. Like RPL26, RPL15 presents the distinctive feature of being required both for 60S subunit formation and for efficient cleavage of the internal transcribed spacer 1. In addition, we detected five deletions in RP genes in which mutations have been previously shown to cause DBA: one each in RPS19, RPS24, and RPS26, and two in RPS17. Pre-ribosomal RNA processing was affected in cells established from the patients bearing these deletions, suggesting a possible molecular basis for their pathological effect. These data identify RPL15 as a new gene involved in DBA and further support the presence of large deletions in RP genes in DBA patients.


Assuntos
Anemia de Diamond-Blackfan/genética , Deleção de Genes , Proteínas Ribossômicas/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Mutação , RNA Ribossômico/análise , RNA Ribossômico/genética , RNA Interferente Pequeno , Proteínas Ribossômicas/metabolismo
12.
J Clin Invest ; 122(7): 2439-43, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22706301

RESUMO

Diamond-Blackfan anemia (DBA) is a hypoplastic anemia characterized by impaired production of red blood cells, with approximately half of all cases attributed to ribosomal protein gene mutations. We performed exome sequencing on two siblings who had no known pathogenic mutations for DBA and identified a mutation in the gene encoding the hematopoietic transcription factor GATA1. This mutation, which occurred at a splice site of the GATA1 gene, impaired production of the full-length form of the protein. We further identified an additional patient carrying a distinct mutation at the same splice site of the GATA1 gene. These findings provide insight into the pathogenesis of DBA, showing that the reduction in erythropoiesis associated with the disease can arise from causes other than defects in ribosomal protein genes. These results also illustrate the multifactorial role of GATA1 in human hematopoiesis.


Assuntos
Anemia de Diamond-Blackfan/genética , Exoma , Fator de Transcrição GATA1/genética , Sequência de Bases , Estudos de Casos e Controles , Análise Mutacional de DNA , Fator de Transcrição GATA1/metabolismo , Estudos de Associação Genética , Hematopoese , Humanos , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Deleção de Sequência , Adulto Jovem
13.
Hum Mutat ; 33(7): 1037-44, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22431104

RESUMO

Diamond-Blackfan anemia (DBA) is an inherited form of pure red cell aplasia that usually presents in infancy or early childhood and is associated with congenital malformations in ∼30-50% of patients. DBA has been associated with mutations in nine ribosomal protein (RP) genes in about 53% of patients. We completed a large-scale screen of 79 RP genes by sequencing 16 RP genes (RPL3, RPL7, RPL8, RPL10, RPL14, RPL17, RPL19, RPL23A, RPL26, RPL27, RPL35, RPL36A, RPL39, RPS4X, RPS4Y1, and RPS21) in 96 DBA probands. We identified a de novo two-nucleotide deletion in RPL26 in one proband associated with multiple severe physical abnormalities. This mutation gives rise to a remarkable ribosome biogenesis defect that affects maturation of both the small and the large subunits. We also found a deletion in RPL19 and missense mutations in RPL3 and RPL23A, which may be variants of unknown significance. Together with RPL5, RPL11, and RPS7, RPL26 is the fourth RP regulating p53 activity that is linked to DBA.


Assuntos
Anormalidades Múltiplas/genética , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/metabolismo , Mutação da Fase de Leitura/genética , RNA Ribossômico/genética , Proteínas Ribossômicas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Northern Blotting , Western Blotting , Células HeLa , Humanos , RNA Interferente Pequeno , Proteínas Ribossômicas/genética , Proteína Supressora de Tumor p53/genética
14.
Am J Hum Genet ; 86(2): 222-8, 2010 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-20116044

RESUMO

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 associated with mutations in seven ribosomal protein (RP) genes, RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, and RPS7, in about 43% of patients. To continue our large-scale screen of RP genes in a DBA population, we sequenced 35 ribosomal protein genes, RPL15, RPL24, RPL29, RPL32, RPL34, RPL9, RPL37, RPS14, RPS23, RPL10A, RPS10, RPS12, RPS18, RPL30, RPS20, RPL12, RPL7A, RPS6, RPL27A, RPLP2, RPS25, RPS3, RPL41, RPL6, RPLP0, RPS26, RPL21, RPL36AL, RPS29, RPL4, RPLP1, RPL13, RPS15A, RPS2, and RPL38, in our DBA patient cohort of 117 probands. We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands. Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA. This accumulation is consistent with the phenotype observed in HeLa cells after knockdown of RPS10 or RPS26 expression with siRNAs, which indicates that mutations in the RPS10 and RPS26 genes in DBA patients affect the function of the proteins in rRNA processing.


Assuntos
Anemia de Diamond-Blackfan/genética , Mutação/genética , Proteínas Ribossômicas/genética , Sequência de Bases , Humanos , Processamento Pós-Transcricional do RNA
15.
Br J Haematol ; 148(4): 611-22, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19958353

RESUMO

Diamond Blackfan anaemia (DBA) is a severe congenital failure of erythropoiesis. Despite mutations in one of several ribosome protein genes, including RPS19, the cause of the erythroid specificity is still a mystery. We hypothesized that, because the chromatin of late erythroid cells becomes condensed and transcriptionally inactive prior to enucleation, the rapidly proliferating immature cells require very high ribosome synthetic rates. RNA biogenesis was measured in primary mouse fetal liver erythroid progenitor cells; during the first 24 h, cell number increased three to fourfold while, remarkably, RNA content increased sixfold, suggesting an accumulation of an excess of ribosomes during early erythropoiesis. Retrovirus infected siRNA RPS19 knockdown cells showed reduced proliferation but normal differentiation, and cell cycle analysis showed a G1/S phase delay. p53 protein was increased in the knockdown cells, and the mRNA level for p21, a transcriptional target of p53, was increased. Furthermore, we show that RPS19 knockdown decreased MYB protein, and Kit mRNA was reduced, as was the amount of cell surface KIT protein. Thus, in this small hairpin RNA murine model of DBA, RPS19 insufficient erythroid cells may proliferate poorly because of p53-mediated cell cycle arrest, and also because of decreased expression of the key erythroid signalling protein KIT.


Assuntos
Anemia de Diamond-Blackfan/genética , Eritropoese/genética , Anemia de Diamond-Blackfan/patologia , Anemia de Diamond-Blackfan/fisiopatologia , Diferenciação Celular/genética , Proliferação de Células , Células Cultivadas , Fase G1/genética , Técnicas de Silenciamento de Genes , Genes myb , Humanos , Fígado/citologia , Fígado/embriologia , RNA/biossíntese , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Proteínas Ribossômicas/genética , Proteína Supressora de Tumor p53/metabolismo
16.
Am J Hum Genet ; 83(6): 769-80, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19061985

RESUMO

Diamond-Blackfan anemia (DBA), a congenital bone-marrow-failure syndrome, is characterized by red blood cell aplasia, macrocytic anemia, clinical heterogeneity, and increased risk of malignancy. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital anomalies that are present in approximately 30%-50% of patients. The disease has been associated with mutations in four ribosomal protein (RP) genes, RPS19, RPS24, RPS17, and RPL35A, in about 30% of patients. However, the genetic basis of the remaining 70% of cases is still unknown. Here, we report the second known mutation in RPS17 and probable pathogenic mutations in three more RP genes, RPL5, RPL11, and RPS7. In addition, we identified rare variants of unknown significance in three other genes, RPL36, RPS15, and RPS27A. Remarkably, careful review of the clinical data showed that mutations in RPL5 are associated with multiple physical abnormalities, including craniofacial, thumb, and heart anomalies, whereas isolated thumb malformations are predominantly present in patients carrying mutations in RPL11. We also demonstrate that mutations of RPL5, RPL11, or RPS7 in DBA cells is associated with diverse defects in the maturation of ribosomal RNAs in the large or the small ribosomal subunit production pathway, expanding the repertoire of ribosomal RNA processing defects associated with DBA.


Assuntos
Anemia de Diamond-Blackfan/genética , Fissura Palatina/genética , Mutação , Proteínas Ribossômicas/genética , Polegar/anormalidades , Humanos , Subunidades Ribossômicas Maiores/genética , Subunidades Ribossômicas Menores/genética
17.
Blood ; 112(5): 1582-92, 2008 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-18535205

RESUMO

Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, congenital abnormalities, and cancer predisposition. Small ribosomal subunit genes RPS19, RPS24, and RPS17 are mutated in approximately one-third of patients. We used a candidate gene strategy combining high-resolution genomic mapping and gene expression microarray in the analysis of 2 DBA patients with chromosome 3q deletions to identify RPL35A as a potential DBA gene. Sequence analysis of a cohort of DBA probands confirmed involvement RPL35A in DBA. shRNA inhibition shows that Rpl35a is essential for maturation of 28S and 5.8S rRNAs, 60S subunit biogenesis, normal proliferation, and cell survival. Analysis of pre-rRNA processing in primary DBA lymphoblastoid cell lines demonstrated similar alterations of large ribosomal subunit rRNA in both RPL35A-mutated and some RPL35A wild-type patients, suggesting additional large ribosomal subunit gene defects are likely present in some cases of DBA. These data demonstrate that alterations of large ribosomal subunit proteins cause DBA and support the hypothesis that DBA is primarily the result of altered ribosomal function. The results also establish that haploinsufficiency of large ribosomal subunit proteins contributes to bone marrow failure and potentially cancer predisposition.


Assuntos
Anemia de Diamond-Blackfan/genética , Mutação , Proteínas Ribossômicas/genética , Sequência de Aminoácidos , Anemia de Diamond-Blackfan/metabolismo , Anemia de Diamond-Blackfan/patologia , Apoptose/genética , Sequência de Bases , Estudos de Casos e Controles , Linhagem Celular , Proliferação de Células , Deleção Cromossômica , Mapeamento Cromossômico , Cromossomos Humanos Par 3/genética , Estudos de Coortes , DNA/genética , Feminino , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Processamento Pós-Transcricional do RNA , RNA Interferente Pequeno/genética , Proteínas Ribossômicas/metabolismo , Ribossomos/metabolismo
18.
Am J Hum Genet ; 79(6): 1110-8, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17186470

RESUMO

Diamond-Blackfan anemia (DBA) is a rare congenital red-cell aplasia characterized by anemia, bone-marrow erythroblastopenia, and congenital anomalies and is associated with heterozygous mutations in the ribosomal protein (RP) S19 gene (RPS19) in approximately 25% of probands. We report identification of de novo nonsense and splice-site mutations in another RP, RPS24 (encoded by RPS24 [10q22-q23]) in approximately 2% of RPS19 mutation-negative probands. This finding strongly suggests that DBA is a disorder of ribosome synthesis and that mutations in other RP or associated genes that lead to disrupted ribosomal biogenesis and/or function may also cause DBA.


Assuntos
Anemia de Diamond-Blackfan/genética , Mutação , Proteínas Ribossômicas/genética , Processamento Alternativo , Sequência de Bases , Células da Medula Óssea/citologia , Células da Medula Óssea/fisiologia , Estudos de Casos e Controles , Células Cultivadas , Feminino , Regulação da Expressão Gênica , Ligação Genética , Humanos , Masculino , Dados de Sequência Molecular , Valores de Referência , Proteínas Ribossômicas/metabolismo , Ribossomos/genética , Ribossomos/metabolismo
19.
Br J Haematol ; 135(2): 149-57, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16942586

RESUMO

Diamond-Blackfan anaemia (DBA) is a congenital anaemia and broad developmental disease that develops soon after birth. The anaemia is due to failure of erythropoiesis, with normal platelet and myeloid lineages, and it can be managed with steroids, blood transfusions, or stem cell transplantation. Normal erythropoiesis after transplantation shows that the defect is intrinsic to an erythroid precursor. DBA is inherited in about 10-20% of cases, and genetic studies have identified mutations in a ribosomal protein gene, RPS19, in 25% of cases; there is evidence for involvement of at least two other genes. In yeast, RPS19 deletion leads to a block in ribosomal RNA biogenesis. The critical question is how mutations in RPS19 lead to the failure of proliferation and differentiation of erythroid progenitors. While this question has not yet been answered, understanding the biology of DBA may provide insight not only into the defect in erythropoisis, but also into the other developmental abnormalities that are present in about 40% of patients, and into the cancer predisposition that is inherent to DBA.


Assuntos
Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/fisiopatologia , Animais , Modelos Animais de Doenças , Eritropoese/genética , Humanos , Camundongos , Camundongos Knockout , Mutação , Proteínas Ribossômicas/genética
20.
Stem Cells ; 24(9): 2034-44, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16741228

RESUMO

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. We found several ribosomal protein genes downregulated in all DBA progenitors. Apoptosis genes, such as TNFRSF10B and FAS, transcriptional control genes, including the erythropoietic transcription factor MYB (encoding c-myb), and translational genes were greatly dysregulated, mostly in diseased erythroid cells. Cancer-related genes, including RAS family oncogenes and tumor suppressor genes, were significantly dysregulated in all diseased progenitors. In addition, our results provide evidence that RPS19 mutations lead to codownregulation of multiple ribosomal protein genes, as well as downregulation of genes involved in translation in DBA cells. In conclusion, the altered expression of cancer-related genes suggests a molecular basis for malignancy in DBA. Downregulation of c-myb expression, which causes complete failure of fetal liver erythropoiesis in knockout mice, suggests a link between RPS19 mutations and reduced erythropoiesis in DBA.


Assuntos
Anemia de Diamond-Blackfan/genética , Apoptose/genética , Regulação da Expressão Gênica , Neoplasias/genética , Biossíntese de Proteínas/genética , Proteínas Ribossômicas/genética , Transcrição Genética , Adulto , Animais , Estudos de Casos e Controles , Separação Celular , Células Precursoras Eritroides/citologia , Células Precursoras Eritroides/metabolismo , Células Precursoras Eritroides/patologia , Feminino , Genoma Humano/genética , Humanos , Masculino , Camundongos , Análise em Microsséries , Mutação/genética , Proteínas Proto-Oncogênicas c-myb/genética , RNA Ribossômico 18S/genética , Reprodutibilidade dos Testes
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