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1.
Rinsho Ketsueki ; 60(5): 408-416, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31168006

RESUMO

Sideroblastic anemia (SA) signifies a group of heterogeneous congenital and acquired disorders characterized by anemia and the presence of ring sideroblasts in the bone marrow. Congenital SA is a rare disease caused by mutations of genes involved in heme biosynthesis, iron-sulfur cluster biosynthesis, and mitochondrial protein synthesis. In addition, SA can occur after exposure to certain drugs or alcohol and because of copper deficiency (secondary SA). Of note, SA also correlates with myelodysplastic syndrome (idiopathic SA). Recent progress in the genome analysis technology has enabled the identification of novel causative genes for SA, elucidating the molecular pathophysiology of these disorders. Accordingly, the significance of genetic diagnosis for SA has been increasing. This review discusses the current understanding of genetic mutations involved in the pathophysiology of SA.


Assuntos
Anemia Sideroblástica/genética , Humanos , Mutação
2.
Int J Mol Sci ; 19(7)2018 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-29958424

RESUMO

Biosynthesis of heme represents a complex process that involves multiple stages controlled by different enzymes. The first of these proteins is a pyridoxal 5′-phosphate (PLP)-dependent homodimeric enzyme, 5-aminolevulinate synthase (ALAS), that catalyzes the rate-limiting step in heme biosynthesis, the condensation of glycine with succinyl-CoA. Genetic mutations in human erythroid-specific ALAS (ALAS2) are associated with two inherited blood disorders, X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP). XLSA is caused by diminished ALAS2 activity leading to decreased ALA and heme syntheses and ultimately ineffective erythropoiesis, whereas XLPP results from “gain-of-function” ALAS2 mutations and consequent overproduction of protoporphyrin IX and increase in Zn2+-protoporphyrin levels. All XLPP-linked mutations affect the intrinsically disordered C-terminal tail of ALAS2. Our earlier molecular dynamics (MD) simulation-based analysis showed that the activity of ALAS2 could be regulated by the conformational flexibility of the active site loop whose structural features and dynamics could be changed due to mutations. We also revealed that the dynamic behavior of the two protomers of the ALAS2 dimer differed. However, how the structural dynamics of ALAS2 active site loop and C-terminal tail dynamics are related to each other and contribute to the homodimer asymmetry remained unanswered questions. In this study, we used bioinformatics and computational biology tools to evaluate the role(s) of the C-terminal tail dynamics in the structure and conformational dynamics of the murine ALAS2 homodimer active site loop. To assess the structural correlation between these two regions, we analyzed their structural displacements and determined their degree of correlation. Here, we report that the dynamics of ALAS2 active site loop is anti-correlated with the dynamics of the C-terminal tail and that this anti-correlation can represent a molecular basis for the functional and dynamic asymmetry of the ALAS2 homodimer.


Assuntos
5-Aminolevulinato Sintetase/química , Anemia Sideroblástica/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Heme/química , 5-Aminolevulinato Sintetase/genética , Anemia Sideroblástica/patologia , Animais , Domínio Catalítico , Biologia Computacional , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Heme/biossíntese , Heme/genética , Humanos , Camundongos , Simulação de Dinâmica Molecular , Mutação/genética , Multimerização Proteica/genética
3.
Gene ; 668: 182-189, 2018 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-29787825

RESUMO

Congenital sideroblastic anemia (CSA) is a series of rare, heterogeneous disorders, characterized by iron overload in the mitochondria of erythroblasts and ringed sideroblasts in bone marrow. In recent years, rapid development of next-generation sequencing technology brings great advance in understanding of genetic and pathophysiologic features of CSA. Based on the pathophysiology of mitochondrial iron metabolism, causative genes of CSA can be divided into three subtypes: heme biosynthesis related; iron­sulfur cluster biosynthesis and transportation related; and mitochondrial respiratory chain synthesis related. Patients with CSA present various clinical manifestation due to relevant mutation gene and require different treatment strategies. The recognition of the causative genes and evolution of pathogenicity is critical. In this review, we summarize the recent progress in mutation genes of CSA, and its potential role in the pathogenesis, diagnosis and treatment.


Assuntos
Anemia Sideroblástica/genética , Mutação , Anemia Sideroblástica/congênito , Anemia Sideroblástica/metabolismo , Heme/biossíntese , Humanos , Ferro/metabolismo , Proteínas Mitocondriais/biossíntese
6.
Int J Hematol ; 107(1): 44-54, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29139060

RESUMO

Sideroblastic anemias are anemic disorders characterized by the presence of ring sideroblasts in a patient's bone marrow. These disorders are typically divided into two types, congenital or acquired sideroblastic anemia. Recently, several genes were reported as responsible for congenital sideroblastic anemia; however, the relationship between the function of the gene products and ring sideroblasts is largely unclear. In this review article, we will focus on the iron metabolism in erythroid cells as well as in patients with congenital sideroblastic anemia.


Assuntos
Anemia Sideroblástica/congênito , Anemia Sideroblástica/genética , Células Eritroides/metabolismo , Ferro/metabolismo , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Anemia Sideroblástica/sangue , Anemia Sideroblástica/metabolismo , Ataxia Cerebelar , Cromossomos Humanos X/genética , Complexo I de Transporte de Elétrons/deficiência , Complexo I de Transporte de Elétrons/genética , Feminino , Glutarredoxinas/genética , Proteínas de Choque Térmico HSP70/genética , Heme/biossíntese , Humanos , Erros Inatos do Metabolismo Lipídico , Síndrome MELAS , Masculino , Doenças Mitocondriais , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas Mitocondriais/genética , Doenças Musculares , Mutação
8.
Blood Cells Mol Dis ; 66: 11-18, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28772256

RESUMO

The most frequent germline mutations responsible for non syndromic congenital sideroblastic anemia are identified in ALAS2 and SLC25A38 genes. Iron overload is a key issue and optimal chelation therapy should be used to limit its adverse effects on the development of children. Our multicentre retrospective descriptive study compared the strategies for diagnosis and management of congenital sideroblastic anemia during the follow-up of six patients with an ALAS2 mutation and seven patients with an SLC25A38 mutation. We described in depth the clinical, biological and radiological phenotype of these patients at diagnosis and during follow-up and highlighted our results with a review of available evidence and data on the management strategies for congenital sideroblastic anemia. This report confirms the considerable variability in manifestations among patients with ALAS2 or SLC25A38 mutations and draws attention to differences in the assessment and the monitoring of iron overload and its complications. The use of an international registry would certainly help defining recommendations for the management of these rare disorders to improve patient outcome.


Assuntos
5-Aminolevulinato Sintetase/genética , Anemia Sideroblástica/congênito , Proteínas de Transporte da Membrana Mitocondrial/genética , Anemia Sideroblástica/genética , Criança , Humanos , Sobrecarga de Ferro , Fenótipo , Estudos Retrospectivos
10.
J Pediatr Hematol Oncol ; 39(6): 463-465, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28731922

RESUMO

Sideroblastic anemias are a rare group of disorders resulting from defective iron incorporation during heme synthesis and hence characterized by anemia and presence of ringed sideroblasts in bone marrow. The most common form is an X-linked disorder caused by mutations in ALAS2 gene. In the current paper, a case of X-linked sideroblastic anemia caused by a novel homozygous deletional mutation in exon 10 of ALAS2 gene is presented. The female infant developed moderately severe anemia at 6 months of age, which did not improve despite adequate nutritional support. The diagnosis was suspected considering a high plasma ferritin of 740.9 µg/L. The protein structure as predicted by SWISS model was a monomeric form rather than wild-type homodimer, resulting in marked loss of function and protein instability.


Assuntos
5-Aminolevulinato Sintetase/genética , Anemia Sideroblástica/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação , Feminino , Ferritinas/sangue , Deleção de Genes , Humanos , Lactente , Modelos Moleculares , Fenótipo , Estabilidade Proteica , Estrutura Quaternária de Proteína
11.
Ann Clin Lab Sci ; 47(3): 319-322, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28667034

RESUMO

We report a novel ALAS2 gene mutation c.1315A>G (p.Lys439Glu) identified in a family, which caused evidently different hematologic phenotypes. The proband was a 17-year-old man with severe microcytic hypochromic anemia, excessive ring sideroblasts in the bone marrow, and iron overload. A hemizygous ALAS2 mutation in exon 9, c.1315A>G (p.Lys439Glu), was identified through sequence analysis. We assume that this amino acid substitution affects the enzymatic activity of ALAS2 by affecting its interaction with the cofactor pyridoxal 5'-phosphate, since the patient was responsive to pyridoxine treatment. This novel mutation likely accounts for variable hematologic phenotypes in the family of this patient: his 15-year-old hemizygous brother was asymptomatic, while his heterozygous mother was mildly anemic.


Assuntos
5-Aminolevulinato Sintetase/genética , Anemia Sideroblástica/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação de Sentido Incorreto , Piridoxina/uso terapêutico , 5-Aminolevulinato Sintetase/metabolismo , Adolescente , Anemia Sideroblástica/tratamento farmacológico , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Heterozigoto , Humanos , Sobrecarga de Ferro/genética , Masculino , Linhagem , Fenótipo , Fosfato de Piridoxal/metabolismo
14.
Rinsho Ketsueki ; 58(4): 347-352, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-28484165

RESUMO

Sideroblastic anemia is characterized by anemia with ring sideroblasts produced by the bone marrow. Sideroblasts are formed by disutilization and deposit of iron in the mitochondoria. There are two forms of sideroblastic anemia: congenital and acquired. Congenital sideroblastic anemia is caused by mutations in genes involved in heme biosynthesis, iron-sulfur (Fe-S) cluster biogenesis, or mitochondrial metabolism. Although there is a variation in the mutated genes among races, the most common congenital sideroblastic anemia is X-linked sideroblastic anemia caused by mutations in the erythroid-specific δ-aminolevulinate synthase gene, which is the first enzyme of heme biosynthesis in erythroid cells. The most commonly acquired sideroblastic anemia is myelodysplastic syndrome with ring sideroblasts (MDS-RS). It has been shown that the splicing factor 3b subunit 1 (SF3B1) gene, which is a core component of the RNA splicing complex, is highly mutated in MDS-RS, although the underlying mechanism of the onset of the disease by the mutation of the SF3B1 gene remains unclear. Molecular analysis will contribute to the development of effective treatment for congenital and acquired sideroblastic anemia, which are intractable diseases.


Assuntos
Anemia Sideroblástica , 5-Aminolevulinato Sintetase/genética , Anemia Sideroblástica/congênito , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/epidemiologia , Anemia Sideroblástica/genética , Animais , Humanos , Mutação
15.
JAMA Neurol ; 74(6): 686-694, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28395030

RESUMO

Importance: YARS2 mutations have been associated with a clinical triad of myopathy, lactic acidosis, and sideroblastic anemia in predominantly Middle Eastern populations. However, the identification of new patients expands the clinical and molecular spectrum of mitochondrial disorders. Objectives: To review the clinical, molecular, and genetic features of YARS2-related mitochondrial disease and to demonstrate a new Scottish founder variant. Design, Setting, and Participants: An observational case series study was conducted at a national diagnostic center for mitochondrial disease in Newcastle upon Tyne, England, and review of cases published in the literature. Six adults in a well-defined mitochondrial disease cohort and 11 additional cases described in the literature were identified with YARS2 variants between January 1, 2000, and January 31, 2015. Main Outcome and Measures: The spectrum of clinical features and disease progression in unreported and reported patients with pathogenic YARS2 variants. Results: Seventeen patients (median [interquartile range] age at onset, 1.5 [9.8] years) with YARS2-related mitochondrial myopathy were identified. Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy; only 12 patients (71%) manifested with sideroblastic anemia. Hypertrophic cardiomyopathy (9 [53%]) and respiratory insufficiency (8 [47%]) were also prominent clinical features. Central nervous system involvement was rare. Muscle studies showed global cytochrome-c oxidase deficiency in all patients tested and severe, combined respiratory chain complex activity deficiencies. Microsatellite genotyping demonstrated a common founder effect shared between 3 Scottish patients with a p.Leu392Ser variant. Immunoblotting from fibroblasts and myoblasts of an affected Scottish patient showed normal YARS2 protein levels and mild respiratory chain complex defects. Yeast modeling of novel missense YARS2 variants closely correlated with the severity of clinical phenotypes. Conclusions and Relevance: The p.Leu392Ser variant is likely a newly identified founder YARS2 mutation. Testing for pathogenic YARS2 variants should be considered in patients presenting with mitochondrial myopathy, characterized by exercise intolerance and muscle weakness even in the absence of sideroblastic anemia irrespective of ethnicity. Regular surveillance and early treatment for cardiomyopathy and respiratory muscle weakness is advocated because early treatment may mitigate the significant morbidity and mortality associated with this genetic disorder.


Assuntos
Acidose Láctica/genética , Anemia Sideroblástica/genética , Cardiomiopatias/genética , Miopatias Mitocondriais/genética , Debilidade Muscular/genética , Insuficiência Respiratória/genética , Tirosina-tRNA Ligase/genética , Acidose Láctica/etnologia , Acidose Láctica/etiologia , Adulto , Idoso , Anemia Sideroblástica/etnologia , Anemia Sideroblástica/etiologia , Cardiomiopatias/etnologia , Cardiomiopatias/etiologia , Inglaterra/etnologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/etnologia , Debilidade Muscular/etnologia , Debilidade Muscular/etiologia , Mutação , Prognóstico , Insuficiência Respiratória/etnologia , Insuficiência Respiratória/etiologia , Escócia/etnologia
17.
Am J Hematol ; 92(3): 297-310, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28188970

RESUMO

DISEASE OVERVIEW: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). DIAGNOSIS: MDS-RS is a lower risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥ 450 × 10(9)/L and large atypical megakaryocytes (similar to BCR-ABL1 negative MPN). MUTATIONS AND KARYOTYPE: Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2 mutations; with ASXL1/SETBP1 mutations adversely impacting survival. Cytogenetic abnormalities are uncommon in both diseases. RISK STRATIFICATION: Most patients with MDS-RS-SLD are stratified into lower risk groups by the revised-International Prognostic Scoring System (R-IPSS). Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia. Both diseases have a low risk of leukemic TREATMENT: Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs is uncertain.


Assuntos
Anemia Refratária/diagnóstico , Anemia Sideroblástica/diagnóstico , Síndromes Mielodisplásicas/classificação , Trombocitose/diagnóstico , Anemia Refratária/classificação , Anemia Refratária/genética , Anemia Sideroblástica/classificação , Anemia Sideroblástica/genética , Humanos , Mutação , Medição de Risco , Trombocitose/classificação , Trombocitose/genética
18.
Leuk Res ; 56: 82-87, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28222336

RESUMO

Our study aimed to analyze the presence of mutations in SF3B1 and other spliceosome-related genes in myelodysplastic syndromes with ringed sideroblasts (MDS-RS) by combining conventional Sanger and next-generation sequencing (NGS) methods, and to determine the feasibility of this approach in a clinical setting. 122 bone marrow samples from MDS-RS patients were studied. Initially, exons 14 and 15 of the SF3B1 gene were analyzed by Sanger sequencing. Secondly, they were studied by NGS covering besides SF3B1, SRSF2, U2AF1 and ZRSR2 genes. An 86% of all patients showed mutations in the SF3B1 gene. Six of them, which were not identifiable by conventional sequencing in the first diagnostic step, were revealed by NGS. In addition, 19.5% of cases showed mutations in other splicing genes: SRSF2, U2AF1, and ZRSR2. Furthermore, 8.7% of patients had two mutations in SF3B1, SF3B1 and SRSF2, and SF3B1 and U2AF1, while 5.7% showed no mutations in the four spliceosome-related genes analyzed. The combined use of conventional Sanger and NGS allows the identification of mutations in spliceosome-related genes in almost all MDS patients with RS. This two-step approach is affordable and could be useful as a complementary technique in cases with an unclear diagnosis.


Assuntos
Anemia Sideroblástica/genética , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Spliceossomos/genética , Anemia Sideroblástica/diagnóstico , Medula Óssea , Humanos , Métodos , Mutação , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , Análise de Sequência de DNA , Fatores de Processamento de Serina-Arginina/genética , Fator de Processamento U2AF/genética
19.
Nucleic Acids Res ; 45(2): 657-671, 2017 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28123038

RESUMO

The first intronic mutations in the intron 1 GATA site (int-1-GATA) of 5-aminolevulinate synthase 2 (ALAS2) have been identified in X-linked sideroblastic anemia (XLSA) pedigrees, strongly suggesting it could be causal mutations of XLSA. However, the function of this int-1-GATA site during in vivo development remains largely unknown. Here, we generated mice lacking a 13 bp fragment, including this int-1-GATA site (T AGATAA: AGCCCC) and found that hemizygous deletion led to an embryonic lethal phenotype due to severe anemia resulting from a lack of ALAS2 expression, indicating that this non-coding sequence is indispensable for ALAS2 expression in vivo Further analyses revealed that this int-1-GATA site anchored the GATA site in intron 8 (int-8-GATA) and the proximal promoter, forming a long-range loop to enhance ALAS2 expression by an enhancer complex including GATA1, TAL1, LMO2, LDB1 and Pol II at least, in erythroid cells. However, compared with the int-8-GATA site, the int-1-GATA site is more essential for regulating ALAS2 expression through CRISPR/Cas9-mediated site-specific deletion. Therefore, the int-1-GATA site could serve as a valuable site for diagnosing XLSA in cases with unknown mutations.


Assuntos
5-Aminolevulinato Sintetase/genética , Sítios de Ligação , Diferenciação Celular , Células Eritroides/citologia , Células Eritroides/metabolismo , Fator de Transcrição GATA1/metabolismo , Íntrons , Anemia Sideroblástica/genética , Animais , Sequência de Bases , Sistemas CRISPR-Cas , Modelos Animais de Doenças , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Genes Letais , Doenças Genéticas Ligadas ao Cromossomo X/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Hemizigoto , Humanos , Células K562 , Masculino , Mutação , Linhagem , Regiões Promotoras Genéticas , Deleção de Sequência
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