Congenital Sideroblastic Anemias: Iron and Heme Lost in Mitochondrial Translation

Fleming, Mark D.

doi:10.1182/asheducation-2011.1.525

Cited by 85 publications

(98 citation statements)

References 43 publications

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“…In the remaining forms of porphyria, erythrocyte non-heme protoporphyrins generally lie within the reference range [13]. Lead and other heavy metal intoxication [15][16][17] and a variety of sideroblastic [18] and inherited microcytic anemias [19] may also be responsible for alterations in erythrocyte PPIX and ZnPP. A recent study found decreased PPIX fluorescence in erythrocytes from diabetic compared to non-diabetic mice, suggesting the possible use of PPIX as a diagnostic marker for monitoring of diabetes [20].…”

Section: Introductionmentioning

confidence: 99%

Dual‐wavelength excitation for fluorescence‐based quantification of zinc protoporphyrin IX and protoporphyrin IX in whole blood

Hennig

Gruber

Vogeser

et al. 2013

Journal of Biophotonics

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Journal of BIOPHOTONICSQuantification of erythrocyte zinc protoporphyrin IX (ZnPP) and protoporphyrin IX (PPIX), individually or jointly, is useful for the diagnostic evaluation of iron deficiency, iron-restricted erythropoiesis, lead exposure, and porphyrias. A method for simultaneous quantification of ZnPP and PPIX in unwashed blood samples is described, using dual-wavelength excitation to effectively eliminate background fluorescence from other blood constituents. In blood samples from 35 subjects, the results of the dualwavelength excitation method and a reference high performance liquid chromatography (HPLC) assay were closely correlated both for ZnPP (r s ¼ 0.943, p < 0.0001; range 37-689 mmol ZnPP/mol heme, 84-1238 nmol/L) and for PPIX (r s ¼ 0.959, p < 0.0001; range 42-4212 mmol PPIX/mol heme, 93-5394 nmol/L). In addition, for ZnPP, the proposed method is compared with conventional single-wavelength excitation and with commercial front-face fluorimetry of washed erythrocytes and whole blood. We hypothesize that dual-wavelength excitation fluorimetry will provide a new approach to the suppression of background fluorescence in blood and tissue measurements of ZnPP and PPIX.

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Section: Introductionmentioning

confidence: 99%

Dual‐wavelength excitation for fluorescence‐based quantification of zinc protoporphyrin IX and protoporphyrin IX in whole blood

Hennig

Gruber

Vogeser

et al. 2013

Journal of Biophotonics

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“…PUS1 facilitates conversion of uridine to its isomer pseudouridine (ψ), which is thought to stabilize RNA secondary structures. 133 The PUS1 mutations decrease the modification of both mitochondrial and cytoplasmic tRNAs, and the disease is associated with decreases in respiratory complexes I and IV; meanwhile, the mutations in YARS2 result in a global decrease in the abundance and synthesis of mitochondrial respiratory complex proteins encoded by the mitochondrial, but not the nuclear, genome. Although the defects in mitochondrial respiration in patients with diseaseassociated PUS1 and YARS2 mutations are likely to result from impaired mitochondrial protein translation, the mechanism by which these mutations cause accumulation of mitochondrial iron and sideroblastic anemia is not known.…”

Section: Mitochondrial Dysfunction and Autophagy In The Pathogenesis mentioning

confidence: 99%

“…132 Pearson marrow-pancreas syndrome is a disorder characterized by bone marrow and exocrine pancreas insufficiency. 133,134 Patients are heteroplasmic for mitochondrial genomic deletions, with almost half of the patients having a canonical 4,977-bp deletion that involves mtDNA-encoded subunits of respiratory complex I (NADH dehydrogenase), complex IV (cytochrome C oxidase), and complex V (ATP synthase), as well as several mttRNA genes. Patients often present as infants with a variety of signs and symptoms, including failure to thrive, lactic acidosis, malabsorption, myopathy, and liver dysfunction.…”

Section: Mitochondrial Dysfunction and Autophagy In The Pathogenesis mentioning

confidence: 99%

Mitophagy in hematopoietic stem cells

Joshi

Kundu

2013

Autophagy

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“…3 Mutations in a GATA transcription factor-binding site located in a transcriptional enhancer element in intron 1 of the ALAS2 gene have also been reported. 4,5 Most ALAS2 mutations responsible for sideroblastic anemia are partial loss-of-function alleles affecting heme biosynthesis.…”

Section: Classification Of Sideroblastic Anemiasmentioning

confidence: 99%

“…3 The 2 most common congenital sideroblastic anemias are X-linked sideroblastic anemia (XLSA) attributable to germline mutations in ALAS2 and the autosomal recessive sideroblastic anemia attributable to mutations in SLC25A38.…”

Section: Classification Of Sideroblastic Anemiasmentioning

confidence: 99%

Diagnosis and treatment of sideroblastic anemias: from defective heme synthesis to abnormal RNA splicing

Cazzola

Malcovati

2015

Hematology

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The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by the presence of ring sideroblasts in the bone marrow. X-linked sideroblastic anemia (XLSA) is caused by germline mutations in ALAS2. Hemizygous males have a hypochromic microcytic anemia, which is generally mild to moderate and is caused by defective heme synthesis and ineffective erythropoiesis. XLSA is a typical iron-loading anemia; although most patients are responsive to pyridoxine, treatment of iron overload is also important in the management of these patients. Autosomal recessive sideroblastic anemia attributable to mutations in SLC25A38, a member of the mitochondrial carrier family, is a severe disease: patients present in infancy with microcytic anemia, which soon becomes transfusion dependent. Conservative therapy includes regular red cell transfusion and iron chelation, whereas allogenic stem cell transplantation represents the only curative treatment. Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome characterized mainly by anemia attributable to ineffective erythropoiesis. The clinical course of RARS is generally indolent, but there is a tendency to worsening of anemia over time, so that most patients become transfusion dependent in the long run. More than 90% of these patients carry somatic mutations in SF3B1, a gene encoding a core component of the RNA splicing machinery. These mutations cause misrecognition of 3Ј splice sites in downstream genes, resulting in truncated gene products and/or decreased expression attributable to nonsense-mediated RNA decay; this explains the multifactorial pathogenesis of RARS. Variants of RARS include refractory cytopenia with multilineage dysplasia and ring sideroblasts, and RARS associated with marked thrombocytosis; these variants involve additional genetic lesions. Inhibitors of molecules of the transforming growth factor-␤ superfamily have been shown recently to target ineffective erythropoiesis and ameliorate anemia both in animal models of myelodysplastic syndrome and in RARS patients. Learning Objectives• To learn the 2 genes most commonly responsible for congenital sideroblastic anemia • To understand that X-linked sideroblastic anemia is an iron-loading anemia and that treatment of iron overload is at least as important as pyridoxine administration in the management of these patients • To understand that SLC25A38-mutant autosomal recessive sideroblastic anemia is a severe disease whose only curative treatment is allogenic hematopoietic stem cell transplantation • To describe the somatic mutations of RNA splicing machinery that are found in refractory anemia with ring sideroblasts and related myeloid neoplasms • To understand that SF3B1-mutant myelodysplastic syndrome represents a distinct entity • To describe the novel drugs that target ineffective erythropoiesis in patients with refractory anemia with ring sideroblastsThe sideroblastic anemias are a heterogeneous group of disorders characterized by anemia of varying severit...

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Congenital Sideroblastic Anemias: Iron and Heme Lost in Mitochondrial Translation

Cited by 85 publications

References 43 publications

Dual‐wavelength excitation for fluorescence‐based quantification of zinc protoporphyrin IX and protoporphyrin IX in whole blood

Dual‐wavelength excitation for fluorescence‐based quantification of zinc protoporphyrin IX and protoporphyrin IX in whole blood

Mitophagy in hematopoietic stem cells

Diagnosis and treatment of sideroblastic anemias: from defective heme synthesis to abnormal RNA splicing

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