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2.
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.

4.
Blood ; 129(23): 3111-3120, 2017 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-28377399

RESUMO

Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by erythroid hypoplasia, usually without perturbation of other hematopoietic lineages. Approximately 65% of DBA patients with autosomal dominant inheritance have heterozygous mutations or deletions in ribosomal protein (RP) genes while <1% of patients with X-linked inheritance have been identified with mutations in the transcription factor GATA1 Erythroid cells from patients with DBA have not been well characterized, and the mechanisms underlying the erythroid specific effects of either RP or GATA1 associated DBA remain unclear. We have developed an ex vivo culture system to expand peripheral blood CD34+ progenitor cells from patients with DBA and differentiate them into erythroid cells. Cells from patients with RP or GATA1 mutations showed decreased proliferation and delayed erythroid differentiation in comparison with controls. RNA transcript analyses of erythroid cells from controls and patients with RP or GATA1 mutations showed distinctive differences, with upregulation of heme biosynthesis genes prominently in RP-mediated DBA and failure to upregulate components of the translational apparatus in GATA1-mediated DBA. Our data show that dysregulation of translation is a common feature of DBA caused by both RP and GATA1 mutations. This trial was registered at www.clinicaltrials.gov as #NCT00106015.


Assuntos
Anemia de Diamond-Blackfan/genética , Adolescente , Adulto , Anemia de Diamond-Blackfan/sangue , Anemia de Diamond-Blackfan/metabolismo , Estudos de Casos e Controles , Diferenciação Celular/genética , Proliferação de Células/genética , Células Cultivadas , Criança , Pré-Escolar , Células Eritroides/metabolismo , Células Eritroides/patologia , Eritropoese/genética , Feminino , Fator de Transcrição GATA1/genética , Genes Dominantes , Genes Ligados ao Cromossomo X , Humanos , Masculino , Modelos Genéticos , Mutação , Proteínas Ribossômicas/genética , Transcriptoma , Adulto Jovem
5.
Am J Hematol ; 89(10): 985-91, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25042156

RESUMO

Diamond Blackfan anemia (DBA), a syndrome primarily characterized by anemia and physical abnormalities, is one among a group of related inherited bone marrow failure syndromes (IBMFS) which share overlapping clinical features. Heterozygous mutations or single-copy deletions have been identified in 12 ribosomal protein genes in approximately 60% of DBA cases, with the genetic etiology unexplained in most remaining patients. Unlike many IBMFS, for which functional screening assays complement clinical and genetic findings, suspected DBA in the absence of typical alterations of the known genes must frequently be diagnosed after exclusion of other IBMFS. We report here a novel deletion in a child that presented such a diagnostic challenge and prompted development of a novel functional assay that can assist in the diagnosis of a significant fraction of patients with DBA. The ribosomal proteins affected in DBA are required for pre-rRNA processing, a process which can be interrogated to monitor steps in the maturation of 40S and 60S ribosomal subunits. In contrast to prior methods used to assess pre-rRNA processing, the assay reported here, based on capillary electrophoresis measurement of the maturation of rRNA in pre-60S ribosomal subunits, would be readily amenable to use in diagnostic laboratories. In addition to utility as a diagnostic tool, we applied this technique to gene discovery in DBA, resulting in the identification of RPL31 as a novel DBA gene.


Assuntos
Precursores de RNA , Processamento Pós-Transcricional do RNA/genética , RNA Ribossômico , Proteínas Ribossômicas , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/metabolismo , Feminino , Humanos , Lactente , Células K562 , Precursores de RNA/genética , Precursores de RNA/metabolismo , RNA Ribossômico/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Subunidades Ribossômicas Maiores de Eucariotos/genética , Subunidades Ribossômicas Maiores de Eucariotos/metabolismo , Subunidades Ribossômicas Menores de Eucariotos/genética , Subunidades Ribossômicas Menores de Eucariotos/metabolismo
6.
Blood ; 122(14): 2487-90, 2013 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-23943650

RESUMO

Classical 5q- syndrome is an acquired macrocytic anemia of the elderly. Similar to Diamond Blackfan anemia (DBA), an inherited red cell aplasia, the bone marrow is characterized by a paucity of erythroid precursors. RPS14 deletions in combination with other deletions in the region have been implicated as causative of the 5q- syndrome phenotype. We asked whether smaller, less easily detectable deletions could account for a syndrome with a modified phenotype. We employed single-nucleotide polymorphism array genotyping to identify small deletions in patients diagnosed with DBA and other anemias lacking molecular diagnoses. Diminutive mosaic deletions involving RPS14 were identified in a 5-year-old patient with nonclassical DBA and in a 17-year-old patient with myelodysplastic syndrome. Patients with nonclassical DBA and other hypoproliferative anemias may have somatically acquired 5q deletions with RPS14 haploinsufficiency not identified by fluorescence in situ hybridization or cytogenetic testing, thus refining the spectrum of disorders with 5q- deletions.


Assuntos
Anemia de Diamond-Blackfan/genética , Anemia Macrocítica/genética , Análise Citogenética/métodos , Proteínas Ribossômicas/genética , Adolescente , Anemia de Diamond-Blackfan/diagnóstico , Anemia Macrocítica/diagnóstico , Anemia Macrocítica/tratamento farmacológico , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Feminino , Genótipo , Humanos , Fatores Imunológicos/uso terapêutico , Lenalidomida , Fenótipo , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real , Talidomida/análogos & derivados , Talidomida/uso terapêutico
7.
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
8.
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
9.
Blood ; 119(16): 3815-9, 2012 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-22362038

RESUMO

Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by red cell aplasia and congenital anomalies. A predisposition to cancer has been suggested but not quantified by case reports. The DBA Registry of North America (DBAR) is the largest established DBA patient cohort, with prospective follow-up since 1991. This report presents the first quantitative assessment of cancer incidence in DBA. Among 608 patients with 9458 person-years of follow-up, 15 solid tumors, 2 acute myeloid leukemias, and 2 cases of myelodysplastic syndrome were diagnosed at a median age of 41 years in patients who had not received a bone marrow transplant. Cancer incidence in DBA was significantly elevated. The observed-to- expected ratio for all cancers combined was 5.4 (P < .05); significant observed-to-expected ratios were 287 for myelodysplastic syndrome, 28 for acute myeloid leukemia, 36 for colon carcinoma, 33 for osteogenic sarcoma, and 12 for female genital cancers. The median survival was 56 years, and the cumulative incidence of solid tumor/leukemia was approximately 20% by age 46 years. As in Fanconi anemia and dyskeratosis congenita, DBA is both an inherited bone marrow failure syndrome and a cancer predisposition syndrome; cancer risks appear lower in DBA than in Fanconi anemia or dyskeratosis congenita. This trial was registered at www.clinicaltrials.gov as #NCT00106015.


Assuntos
Anemia de Diamond-Blackfan/mortalidade , Anemia de Diamond-Blackfan/terapia , Transplante de Medula Óssea , Hemoglobinúria Paroxística/mortalidade , Neoplasias/mortalidade , Sistema de Registros/estatística & dados numéricos , Adolescente , Adulto , Idoso , Anemia Aplástica , Doenças da Medula Óssea , Criança , Pré-Escolar , Comorbidade , Feminino , Seguimentos , Hemoglobinúria Paroxística/terapia , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
10.
Blood ; 118(26): 6943-51, 2011 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-22045982

RESUMO

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.


Assuntos
Anemia de Diamond-Blackfan/genética , Deleção de Genes , Proteínas Ribossômicas/genética , Northern Blotting , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla/métodos , Técnicas de Genotipagem/métodos , Haploinsuficiência , Humanos , Lactente , Recém-Nascido , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa
11.
Hum Mutat ; 31(12): 1269-79, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20960466

RESUMO

Diamond-Blackfan Anemia (DBA) is characterized by a defect of erythroid progenitors and, clinically, by anemia and malformations. DBA exhibits an autosomal dominant pattern of inheritance with incomplete penetrance. Currently nine genes, all encoding ribosomal proteins (RP), have been found mutated in approximately 50% of patients. Experimental evidence supports the hypothesis that DBA is primarily the result of defective ribosome synthesis. By means of a large collaboration among six centers, we report here a mutation update that includes nine genes and 220 distinct mutations, 56 of which are new. The DBA Mutation Database now includes data from 355 patients. Of those where inheritance has been examined, 125 patients carry a de novo mutation and 72 an inherited mutation. Mutagenesis may be ascribed to slippage in 65.5% of indels, whereas CpG dinucleotides are involved in 23% of transitions. Using bioinformatic tools we show that gene conversion mechanism is not common in RP genes mutagenesis, notwithstanding the abundance of RP pseudogenes. Genotype-phenotype analysis reveals that malformations are more frequently associated with mutations in RPL5 and RPL11 than in the other genes. All currently reported DBA mutations together with their functional and clinical data are included in the DBA Mutation Database.


Assuntos
Anemia de Diamond-Blackfan/genética , Bases de Dados Genéticas , Mutação/genética , Ribossomos/genética , Anemia de Diamond-Blackfan/diagnóstico , Sequência de Bases , Estudos de Associação Genética , Humanos , Dados de Sequência Molecular , Mutagênese/genética , Proteínas Ribossômicas/genética
12.
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
13.
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
14.
Br J Haematol ; 142(6): 859-76, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18671700

RESUMO

Diamond Blackfan anaemia (DBA) is a rare, genetically and clinically heterogeneous, inherited red cell aplasia. Classical DBA affects about seven per million live births and presents during the first year of life. However, as mutated genes have been discovered in DBA, non-classical cases with less distinct phenotypes are being described in adults as well as children. In caring for these patients it is often difficult to have a clear understanding of the treatment options and their outcomes because of the lack of complete information on the natural history of the disease. The purpose of this document is to review the criteria for diagnosis, evaluate the available treatment options, including corticosteroid and transfusion therapies and stem cell transplantation, and propose a plan for optimizing patient care. Congenital anomalies, mode of inheritance, cancer predisposition, and pregnancy in DBA are also reviewed. Evidence-based conclusions will be made when possible; however, as in many rare diseases, the data are often anecdotal and the recommendations are based upon the best judgment of experienced clinicians. The recommendations regarding the diagnosis and management described in this report are the result of deliberations and discussions at an international consensus conference.


Assuntos
Anemia de Diamond-Blackfan/diagnóstico , Anemia de Diamond-Blackfan/terapia , Adulto , Anemia de Diamond-Blackfan/complicações , Anemia de Diamond-Blackfan/genética , Criança , Anormalidades Congênitas/etiologia , Diagnóstico Diferencial , Transfusão de Eritrócitos , Feminino , Predisposição Genética para Doença , Glucocorticoides/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Neoplasias/etiologia , Gravidez , Complicações Hematológicas na Gravidez/terapia , Resultado do Tratamento
15.
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
16.
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
17.
Pediatr Blood Cancer ; 46(5): 558-64, 2006 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-16317735

RESUMO

Diamond Blackfan anemia (DBA) is a heterogeneous genetic disorder characterized by red cell aplasia, congenital anomalies, and a predisposition to cancer. Although incompletely understood, the erythroid failure in DBA appears to result from the accelerated apoptosis of affected erythroid progenitors/precursors. One of what appears to be multiple DBA genes, coding for a ribosomal protein RPS 19, has been cloned. Even within multiplex families individuals may vary dramatically as to the degree of anemia, response to treatment and the presence of congenital anomalies. The Diamond Blackfan Anemia Registry (DBAR), a comprehensive database of pediatric and adult patients with DBA who are enrolled after informed consent, was designed to overcome two significant obstacles encountered in the study of a rare disease; the reporting bias inherent in the literature and the lack of an active patient database. To enroll, patients, their families and their physicians complete a detailed questionnaire. A review of medical records and telephone interviews are performed to complete and clarify the information provided. As of May 1, 2005, 420 patients have been enrolled in the DBAR. Epidemiological, clinical, and laboratory data have been collected and analyzed. The DBAR has provided new information on the clinical presentation, outcome and genetics of DBA as well as a better description of congenital malformations and cancer predisposition. This has resulted both in improved clinical care of patients with DBA as well as providing new insights into the pathophysiology of this complex disorder.


Assuntos
Anemia de Diamond-Blackfan/fisiopatologia , Anemia de Diamond-Blackfan/terapia , Adolescente , Adulto , Anemia de Diamond-Blackfan/epidemiologia , Anemia de Diamond-Blackfan/genética , Pré-Escolar , Eritropoese/genética , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Sistema de Registros , Taxa de Sobrevida , Resultado do Tratamento
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