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Journal of Personalized Medicine Jun 2024The ATP-binding cassette (ABC) transporters are a vast group of 48 membrane proteins, some of which are of notable physiological and clinical importance. Some ABC... (Review)
Review
The ATP-binding cassette (ABC) transporters are a vast group of 48 membrane proteins, some of which are of notable physiological and clinical importance. Some ABC transporters are involved in functions such as the transport of chloride ions, bilirubin, reproductive hormones, cholesterol, and iron. Consequently, genetic or physiological disruption in these functions is manifested in various disease processes like cystic fibrosis, Tangier disease, and sideroblastic anemia. Among other etiologies, primary sideroblastic anemia results from a genetic mutation in the ATP-binding cassette-7 (ABCB7), a member of the ABC transporter family. There are not many articles specifically tackling the disease processes caused by ABC transporters in detail. Some testing methodologies previously reported in the available literature for investigating sideroblastic anemia need updating. Here, we expound on the relevance of ABCB7 as a clinically important ABC transporter and a rare participant in the disease process of Sideroblastic anemia. The other genetic and secondary etiologies of sideroblastic anemia, which do not involve mutations in the ABCB7 protein, are also described. We review the pathophysiology, clinical course, symptoms, diagnosis, and treatment of sideroblastic anemia with a focus on modern technologies for laboratory testing.
PubMed: 38929857
DOI: 10.3390/jpm14060636 -
Blood Jun 2024X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP) are uncommon diseases caused by loss-of-function and gain-of-function mutations, respectively, in...
X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP) are uncommon diseases caused by loss-of-function and gain-of-function mutations, respectively, in the erythroid form of 5-aminolevulinic acid synthetase, ALAS2, which encodes the first enzyme in heme biosynthesis. A related sideroblastic anemia is due to mutations in SLC25A38, which supplies mitochondrial glycine for ALAS2 (SLC25A38-CSA). The lack of viable animal models has limited studies on the pathophysiology and development of therapies for these conditions. Here, using CRISPR-CAS9 gene editing technology, we have generated knock-in mouse models that recapitulate the main features of XLSA and XLPP, and, using conventional conditional gene targeting in embryonic stem cells, we also developed a faithful model of the SLC25A38-CSA. In addition to examining the phenotypes and natural history of each disease, we determine the effect of restriction or supplementation of dietary pyridoxine (vitamin B6), the essential cofactor of ALAS2, on the anemia and porphyria. In addition to the well-documented response of XLSA mutations to pyridoxine supplementation, we also demonstrate the relative insensitivity of the XLPP porphyria, severe sensitivity of the XLSA models, and an extreme hypersensitivity of the SLC25A38-CSA model to pyridoxine deficiency, a phenotype that is not shared with another mouse hereditary anemia model, Hbbth3/+ -thalassemia intermedia. Thus, in addition to generating animal models useful for examining the pathophysiology and treatment of these diseases, we have uncovered an unsuspected conditional synthetic lethality between the heme synthesis-related CSAs and pyridoxine deficiency. These findings have the potential to inform novel therapeutic paradigms for the treatment of these diseases.
PubMed: 38900972
DOI: 10.1182/blood.2023023078 -
Biochemistry Jul 2024The conserved enzyme aminolevulinic acid synthase (ALAS) initiates heme biosynthesis in certain bacteria and eukaryotes by catalyzing the condensation of glycine and...
The conserved enzyme aminolevulinic acid synthase (ALAS) initiates heme biosynthesis in certain bacteria and eukaryotes by catalyzing the condensation of glycine and succinyl-CoA to yield aminolevulinic acid. In humans, the ALAS isoform responsible for heme production during red blood cell development is the erythroid-specific ALAS2 isoform. Owing to its essential role in erythropoiesis, changes in human ALAS2 (hALAS2) function can lead to two different blood disorders. X-linked sideroblastic anemia results from loss of ALAS2 function, while X-linked protoporphyria results from gain of ALAS2 function. Interestingly, mutations in the ALAS2 C-terminal extension can be implicated in both diseases. Here, we investigate the molecular basis for enzyme dysfunction mediated by two previously reported C-terminal loss-of-function variants, hALAS2 V562A and M567I. We show that the mutations do not result in gross structural perturbations, but the enzyme stability for V562A is decreased. Additionally, we show that enzyme stability moderately increases with the addition of the pyridoxal 5'-phosphate (PLP) cofactor for both variants. The variants display differential binding to PLP and the individual substrates compared to wild-type hALAS2. Although hALAS2 V562A is a more active enzyme , it is less efficient concerning succinyl-CoA binding. In contrast, the M567I mutation significantly alters the cooperativity of substrate binding. In combination with previously reported cell-based studies, our work reveals the molecular basis by which hALAS2 C-terminal mutations negatively affect ALA production necessary for proper heme biosynthesis.
Topics: Humans; 5-Aminolevulinate Synthetase; Anemia, Sideroblastic; Genetic Diseases, X-Linked; Loss of Function Mutation; Enzyme Stability; Heme; Porphyrias; Models, Molecular; Mutation; Protoporphyria, Erythropoietic
PubMed: 38888931
DOI: 10.1021/acs.biochem.4c00066 -
Journal of Pediatric Hematology/oncology Jul 2024Primary mitochondrial disorders (PMDs) are known for their pleiotropic manifestations in humans, affecting almost any organ or system at any time. Hematologic... (Review)
Review
Primary mitochondrial disorders (PMDs) are known for their pleiotropic manifestations in humans, affecting almost any organ or system at any time. Hematologic manifestations, such as cytopenias and sideroblastic anemia, occur in 10% to 30% of patients with confirmed PMDs. These can be the initial presenting features or complications that develop over time. Surveillance for these manifestations allows for prompt identification and treatment. This article provides an overview of the pathophysiology underpinning the hematologic effects of mitochondrial dysfunction, discussing the 3 key roles of the mitochondria in hematopoiesis: providing energy for cell differentiation and function, synthesizing heme, and generating iron-sulfur clusters. Subsequently, the diagnosis and management of mitochondrial disorders are discussed, focusing on hematologic manifestations and the specific conditions commonly associated with them. Through this, we aimed to provide a concise point of reference for those considering a mitochondrial cause for a patient's hematologic abnormality, or for those considering a hematologic manifestation in a patient with known or suspected mitochondrial disease.
Topics: Humans; Mitochondrial Diseases; Hematologic Diseases; Mitochondria; Hematopoiesis; Anemia, Sideroblastic
PubMed: 38857202
DOI: 10.1097/MPH.0000000000002890 -
Cureus May 2024Sideroblastic anemia is characterized by anemia, granulocytopenia, and bone marrow findings of vacuolated precursors and ringed sideroblasts. Zinc-induced copper...
Sideroblastic anemia is characterized by anemia, granulocytopenia, and bone marrow findings of vacuolated precursors and ringed sideroblasts. Zinc-induced copper deficiency can present as sideroblastic anemia and neutropenia. We report the case of a previously healthy 74-year-old female who presented with newly discovered sideroblastic anemia as a result of an over-the-counter oral vitamin and mineral supplement. Serum analysis revealed increased zinc levels, decreased copper levels, and a decrease in ceruloplasmin. Bone marrow evaluation revealed ringed sideroblasts and cytoplasmic vacuolization in myeloid precursors. She demonstrated improvement in her hematologic profile with discontinuation of the over-the-counter product and administration of oral copper supplementation. This case highlights the importance of sideroblastic anemia recognition and careful medication review, including over-the-counter supplements.
PubMed: 38846187
DOI: 10.7759/cureus.59796 -
Blood Advances May 2024Among the most common genetic alterations in the myelodysplastic syndromes (MDS) are mutations in the spliceosome gene SF3B1. Such mutations induce specific RNA...
Among the most common genetic alterations in the myelodysplastic syndromes (MDS) are mutations in the spliceosome gene SF3B1. Such mutations induce specific RNA missplicing events, directly promote ring sideroblast (RS) formation, and generally associate with more favorable prognosis. However, not all SF3B1 mutations are the same, and little is known about how distinct hotspots influence disease. Here we report that the E592K variant of SF3B1 associates with high-risk disease features in MDS, including a lack of RS, increased myeloblasts, a distinct co-mutation pattern, and a lack of the favorable survival seen with other SF3B1 mutations. Moreover, compared to other hotspot SF3B1 mutations, E592K induces a unique RNA missplicing pattern, retains an interaction with the splicing factor SUGP1, and preserves normal RNA splicing of the sideroblastic anemia genes TMEM14C and ABCB7. These data have implications for our understanding of the functional diversity of spliceosome mutations, as well as the pathobiology, classification, prognosis, and management of SF3B1-mutant MDS.
PubMed: 38759096
DOI: 10.1182/bloodadvances.2023011260 -
American Journal of Ophthalmology Case... Jun 2024To describe a case with Leber's hereditary optic neuropathy (LHON) like optic atrophy in the presence of gene variant m.8969G > A.
PURPOSE
To describe a case with Leber's hereditary optic neuropathy (LHON) like optic atrophy in the presence of gene variant m.8969G > A.
OBSERVATIONS
A 20-year-old patient with a history of mild developmental delay, mild cognitive impairment, and positional tremor presented with subacute painless visual loss over a few weeks. Mitochondrial genome sequencing revealed a variant in , m.8969G > A (p.Ser148Asn). This variant was previously reported in association with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) and with nephropathy, followed by brain atrophy, muscle weakness and arrhythmias, but not with optic atrophy.
CONCLUSIONS AND IMPORTANCE
Rare variants in can also cause LHON like optic atrophy. It is important to perform further genetic analysis of mitochondrial DNA in genetically unsolved cases suspected of Leber's hereditary optic neuropathy to confirm the clinical diagnosis.
PubMed: 38756953
DOI: 10.1016/j.ajoc.2024.102070 -
American Journal of Biological... May 2024Search for possible associations between bone elemental concentration and the presence of porous skeletal lesions (PSLs), considering the sex, age, and cause of death...
OBJECTIVES
Search for possible associations between bone elemental concentration and the presence of porous skeletal lesions (PSLs), considering the sex, age, and cause of death (COD) of the individuals.
MATERIALS AND METHODS
The sample comprised 107 non-adult individuals (56 females, 51 males) aged 0-20 (x̄ = 13.2, SD = 5.8) from the Coimbra and Lisbon Identified Skeletal Collections. Cribra cranii, orbitalia, humeralis, and femoralis were recorded as present/absent, and elemental concentrations were assessed by portable x-ray fluorescence (pXRF). A multivariate statistical approach was applied.
RESULTS
Well-preserved skeletons with minimal diagenesis showed no sex-related elemental variations or PSL associations. In contrast, age-at-death correlated with elevated Ca, P, Sr, and Pb levels. Cribra cranii increased with age while other cribra declined post-adolescence. Higher concentrations of Fe and lower of S were linked to cribra cranii. Respiratory infections as COD increased the odds of expressing cribra femoralis (OR = 5.25, CI = 1.25-15.14), cribra cranii (OR = 2.91, CI = 0.97-8.69), and cribra orbitalia (OR = 2.76, CI = 1.06-7.24).
DISCUSSION
Feasible pXRF results and low cribra intraobserver error assure replicability. Elevated Ca, P, and Sr in older individuals may relate to skeletal growth, while increased Pb suggests bioaccumulation. Cribra's increase with age reflects different rates of marrow conversion and bone remodeling. Higher Fe and lower S in individuals with cribra cranii possibly reflects poor nutrition, early alcohol use, and sideroblastic anemia, aligning with 19th-20th-century Portugal's living conditions. Respiratory infections increased cribra expression, revealing intricate interplays among inflammation, anemia(s), marrow expansion, and diet. This research highlights a complex scenario and blazes a new path for cribra interpretation.
PubMed: 38747122
DOI: 10.1002/ajpa.24954 -
AIDS (London, England) Jun 2024
Topics: Humans; Oxazines; Pyridones; Heterocyclic Compounds, 3-Ring; Piperazines; Anemia, Sideroblastic; HIV Infections; Male; HIV Integrase Inhibitors; Middle Aged
PubMed: 38691054
DOI: 10.1097/QAD.0000000000003855 -
[Rinsho Ketsueki] the Japanese Journal... 2024
Review
Topics: Anemia, Sideroblastic; Humans; RNA Splicing; Mutation; Animals
PubMed: 38684431
DOI: 10.11406/rinketsu.65.222