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[Rinsho Ketsueki] the Japanese Journal... 2019Sideroblastic anemia (SA) signifies a group of heterogeneous congenital and acquired disorders characterized by anemia and the presence of ring sideroblasts in the bone... (Review)
Review
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.
Topics: Anemia, Sideroblastic; Humans; Mutation
PubMed: 31168006
DOI: 10.11406/rinketsu.60.408 -
Blood Jan 2019The sideroblastic anemias (SAs) are a group of inherited and acquired bone marrow disorders defined by pathological iron accumulation in the mitochondria of erythroid... (Review)
Review
The sideroblastic anemias (SAs) are a group of inherited and acquired bone marrow disorders defined by pathological iron accumulation in the mitochondria of erythroid precursors. Like most hematological diseases, the molecular genetic basis of the SAs has ridden the wave of technology advancement. Within the last 30 years, with the advent of positional cloning, the human genome project, solid-state genotyping technologies, and next-generation sequencing have evolved to the point where more than two-thirds of congenital SA cases, and an even greater proportion of cases of acquired clonal disease, can be attributed to mutations in a specific gene or genes. This review focuses on an analysis of the genetics of these diseases and how understanding these defects may contribute to the design and implementation of rational therapies.
Topics: Anemia, Sideroblastic; Erythroid Precursor Cells; Genetic Diseases, X-Linked; Humans; Iron
PubMed: 30401706
DOI: 10.1182/blood-2018-08-815951 -
Gene Aug 2018Congenital sideroblastic anemia (CSA) is a series of rare, heterogeneous disorders, characterized by iron overload in the mitochondria of erythroblasts and ringed... (Review)
Review
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; iron‑sulfur 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.
Topics: Anemia, Sideroblastic; Heme; Humans; Iron; Mitochondrial Proteins; Mutation
PubMed: 29787825
DOI: 10.1016/j.gene.2018.05.074 -
Hematology/oncology Clinics of North... Aug 2014Sideroblastic anemias (SAs) may be acquired or congenital and share the features of disrupted utilization of iron in the erythroblast, ineffective erythropoiesis, and... (Review)
Review
Sideroblastic anemias (SAs) may be acquired or congenital and share the features of disrupted utilization of iron in the erythroblast, ineffective erythropoiesis, and variable systemic iron overload. Congenital forms can have associated syndromic features or be nonsyndromic, and many of them have mutations in genes encoding proteins involved in heme biosynthesis, iron-sulfur cluster biogenesis, or mitochondrial protein synthesis. The mechanism(s) for the acquired clonal SA is undefined and is under intense study. Precise diagnosis of these disorders rests on careful clinical and laboratory evaluation, including molecular analysis. Supportive treatments usually provide for a favorable prognosis and often for normal survival.
Topics: Anemia, Sideroblastic; Disease Management; Humans; Iron Overload
PubMed: 25064706
DOI: 10.1016/j.hoc.2014.04.008 -
Archives of Internal Medicine Oct 1980
Topics: Anemia, Sideroblastic; Humans
PubMed: 7425762
DOI: No ID Found -
International Journal of Hematology Oct 2010Sideroblastic anemia is characterized by anemia with the emergence of ring sideroblasts in the bone marrow. Ring sideroblasts are erythroblasts characterized by iron... (Review)
Review
Sideroblastic anemia is characterized by anemia with the emergence of ring sideroblasts in the bone marrow. Ring sideroblasts are erythroblasts characterized by iron accumulation in perinuclear mitochondria due to impaired iron utilization. There are two forms of sideroblastic anemia, i.e., inherited and acquired sideroblastic anemia. Inherited sideroblastic anemia is a rare and heterogeneous disease caused by mutations of genes involved in heme biosynthesis, iron-sulfur (Fe-S) cluster biogenesis, or Fe-S cluster transport, and mitochondrial metabolism. The most common inherited sideroblastic anemia is X-linked sideroblastic anemia (XLSA) caused by mutations of the erythroid-specific δ-aminolevulinate synthase gene (ALAS2), which is the first enzyme of heme biosynthesis in erythroid cells. Sideroblastic anemia due to SLC25A38 gene mutations, which is a mitochondrial transporter, is the next most common inherited sideroblastic anemia. Other forms of inherited sideroblastic anemia are very rare, and accompanied by impaired function of organs other than hematopoietic tissue, such as the nervous system, muscle, or exocrine glands due to impaired mitochondrial metabolism. Moreover, there are still significant numbers of cases with genetically undefined inherited sideroblastic anemia. Molecular analysis of these cases will contribute not only to the development of effective treatment, but also to the understanding of mitochondrial iron metabolism.
Topics: Anemia, Sideroblastic; Animals; Genetic Predisposition to Disease; Humans; Mitochondria; Mutation
PubMed: 20848343
DOI: 10.1007/s12185-010-0688-4 -
Hospital Practice (Office Ed.) Apr 1991
Topics: Anemia, Sideroblastic; Heme; Humans; Iron
PubMed: 2010487
DOI: 10.1080/21548331.1991.11704283 -
Pediatrics International : Official... Dec 2013Sideroblastic anemias are heterogeneous congenital and acquired disorders characterized by anemia and the presence of ringed sideroblasts in the bone marrow. Congenital... (Review)
Review
Sideroblastic anemias are heterogeneous congenital and acquired disorders characterized by anemia and the presence of ringed sideroblasts in the bone marrow. Congenital sideroblastic anemia (CSA) is a rare disease caused by mutations of genes involved in heme biosynthesis, iron-sulfur [Fe-S] cluster biosynthesis, and mitochondrial protein synthesis. The most common form is X-linked sideroblastic anemia, due to mutations in the erythroid-specific δ-aminolevulinate synthase (ALAS2), which is the first enzyme of the heme biosynthesis pathway in erythroid cells. Other known etiologies include mutations in the erythroid specific mitochondrial transporter (SLC25A38), adenosine triphosphate (ATP) binding cassette B7 (ABCB7), glutaredoxin 5 (GLRX5), thiamine transporter SLC19A2, the RNA-modifying enzyme pseudouridine synthase (PUS1), and mitochondrial tyrosyl-tRNA synthase (YARS2), as well as mitochondrial DNA deletions. Due to its rarity, however, there have been few systematic pathophysiological and genetic investigations focusing on sideroblastic anemia. Therefore, a nationwide survey of sideroblastic anemia was conducted in Japan to investigate the epidemiology and pathogenesis of this disease. This review will cover the findings of this recent survey and summarize the current understanding of the pathophysiology and genetic mutations involved in CSA.
Topics: Anemia, Sideroblastic; Child; Genetic Diseases, X-Linked; Humans; Mutation
PubMed: 24003969
DOI: 10.1111/ped.12217 -
JAMA
Topics: Aged; Aged, 80 and over; Anemia, Sideroblastic; Bone Marrow; Humans; Isoniazid; Male
PubMed: 3573277
DOI: No ID Found -
Scientific Reports May 2022X-linked sideroblastic anemia (XLSA), the most common form of congenital sideroblastic anemia, is caused by a germline mutation in the erythroid-specific...
X-linked sideroblastic anemia (XLSA), the most common form of congenital sideroblastic anemia, is caused by a germline mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene. In XLSA, defective heme biosynthesis leads to ring sideroblast formation because of excess mitochondrial iron accumulation. In this study, we introduced ALAS2 missense mutations on human umbilical cord blood-derived erythroblasts; hereafter, we refer to them as XLSA clones. XLSA clones that differentiated into mature erythroblasts showed an increased frequency of ring sideroblast formation with impaired hemoglobin biosynthesis. The expression profiling revealed significant enrichment of genes involved in ferroptosis, which is a form of regulated cell death induced by iron accumulation and lipid peroxidation. Notably, treatment with erastin, a ferroptosis inducer, caused a higher proportion of cell death in XLSA clones. XLSA clones exhibited significantly higher levels of intracellular lipid peroxides and enhanced expression of BACH1, a regulator of iron metabolism and potential accelerator of ferroptosis. In XLSA clones, BACH1 repressed genes involved in iron metabolism and glutathione synthesis. Collectively, defective heme biosynthesis in XLSA clones could confer enhanced BACH1 expression, leading to increased susceptibility to ferroptosis. The results of our study provide important information for the development of novel therapeutic targets for XLSA.
Topics: 5-Aminolevulinate Synthetase; Anemia, Sideroblastic; Erythroblasts; Ferroptosis; Genetic Diseases, X-Linked; Heme; Humans; Iron; Mutation
PubMed: 35637209
DOI: 10.1038/s41598-022-12940-9