Atypical erythroblastosis in a patient with Diamond–Blackfan anemia who developed del(20q) myelodysplasia

Sonoda, Motoshi; Ishimura, Masataka; Ichimiya, Yuko; Terashi, Eiko; Eguchi, Katsuhide; Sakai, Yasunari; Takada, Hidetoshi; Hama, Asahito; Kanno, Hitoshi; Toki, Tsutomu; Ito, Etsuro; Ohga, Shouichi

doi:10.1007/s12185-018-2424-4

Cited by 6 publications

(6 citation statements)

References 23 publications

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“…Mutations in human HMGCS1 have not been associated with disease, but there are 8 congenital anomalies that occur as a consequence of mutations within other enzymes of the CSP. [5][6][7][8][9][10][11]13,51 These congenital anomalies are characterized by diverse phenotypes, 7,21,[51][52][53] and mutations in the zebrafish hmgcs1 gene mimic these disorders, resulting in a multiple congenital anomaly syndrome. Therefore, zebrafish with mutations in hmgcs1 have the potential to reveal novel cellular and molecular mechanisms underlying individual phenotypes across multiple genetic disorders.…”

Section: Discussionmentioning

confidence: 99%

“…For example, Diamond-Blackfan anemia can result from mutations in the transcription factor GATA1. [12][13][14] GATA1 is the founding member of the GATA family of zinc finger transcription factors 15 that interacts with a multitude of other proteins such as Friend of GATA, EKLF, SP1, p300, and PU.1 to promote erythropoiesis. 16 Cholesterol is 1 known regulator of RBC function because it maintains the structure and integrity of the RBC membrane and aids in the protection against oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

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Mutations in the zebrafish hmgcs1 gene reveal a novel function for isoprenoids during red blood cell development

et al. 2019

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Erythropoiesis is the process by which new red blood cells (RBCs) are formed and defects in this process can lead to anemia or thalassemia. The GATA1 transcription factor is an established mediator of RBC development. However, the upstream mechanisms that regulate the expression of GATA1 are not completely characterized. Cholesterol is 1 potential upstream mediator of GATA1 expression because previously published studies suggest that defects in cholesterol synthesis disrupt RBC differentiation. Here we characterize RBC development in a zebrafish harboring a single missense mutation in the hmgcs1 gene (Vu57 allele). hmgcs1 encodes the first enzyme in the cholesterol synthesis pathway and mutation of hmgcs1 inhibits cholesterol synthesis. We analyzed the number of RBCs in hmgcs1 mutants and their wild-type siblings. Mutation of hmgcs1 resulted in a decrease in the number of mature RBCs, which coincides with reduced gata1a expression. We combined these experiments with pharmacological inhibition and confirmed that cholesterol and isoprenoid synthesis are essential for RBC differentiation, but that gata1a expression is isoprenoid dependent. Collectively, our results reveal 2 novel upstream regulators of RBC development and suggest that appropriate cholesterol homeostasis is critical for primitive erythropoiesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutations in the zebrafish hmgcs1 gene reveal a novel function for isoprenoids during red blood cell development

et al. 2019

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“…Here we show that cholesterol and isoprenoids regulate erythropoiesis using a zebrafish harboring mutations in the hmgcs1 gene (Vu57 allele). Mutations in human HMGCS1 have not been associated with disease, but there are 8 congenital anomalies that occur as a consequence of mutations within other enzymes of the CSP [5][6][7][8][9][10][11]13,48 . These congenital anomalies are characterized by diverse phenotypes 7,21,[48][49][50] and mutations in the zebrafish hmgcs1 gene mimics these disorders resulting in a multiple congenital anomaly syndrome.…”

Section: Discussionmentioning

confidence: 99%

“…Genetic disorders of RBCs have revealed critical mediators of erythropoiesis [7][8][9][10][11] , many of which include transcription factors. For example, Diamond-Blackfan anemia can result from mutations in the transcription factor GATA1 [12][13][14] . GATA1 is the founding member of the GATA family of zinc finger transcription factors 15 and interacts with a multitude of other proteins such as Friend of GATA (FOG), EKLF, SP1, p300 and PU.1 to promote erythropoiesis 16 .…”

Section: Introductionmentioning

confidence: 99%

Mutations in the zebrafishhmgcs1gene reveal a novel function for isoprenoids during red blood cell development

Hernández

Castro

Reyes-Nava

et al. 2018

Preprint

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word count: 187 Number of figures and tables: 5 Number of references: 72 Key Points 1. The products of the cholesterol synthesis pathway regulate red blood cell development during primitive erythropoiesis. 2. Isoprenoids regulate erythropoiesis by modulating the expression of the GATA1 transcription factor. AbstractErythropoiesis is the process by which new red blood cells (RBCs) are formed and defects in this process can lead to anemia or thalassemia. The GATA1 transcription factor is an established mediator of RBC development. However, the upstream mechanisms that regulate the expression of GATA1 are not completely characterized. Cholesterol is one potential upstream mediator of GATA1 expression because previously published studies suggest that defects in cholesterol synthesis disrupt RBC differentiation. Here we characterize RBC development in a zebrafish harboring a single missense mutation in the hmgcs1 gene (Vu57 allele). hmgcs1 encodes the first enzyme in the cholesterol synthesis pathway and mutation of hmgcs1 inhibits cholesterol synthesis. We analyzed the number of RBCs in hmgcs1 mutants and their wildtype siblings. Mutation of hmgcs1 resulted in a decrease in the number of mature RBCs, which coincides with reduced gata1a expression. We combined these experiments with pharmacological inhibition and confirmed that cholesterol and isoprenoid synthesis are essential for RBC differentiation, but that gata1a expression is isoprenoid dependent. Collectively, our results reveal two novel upstream regulators of RBC development and suggest that appropriate cholesterol homeostasis is critical for primitive erythropoiesis.

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“…However, hematologists continue to face difficulties in the diagnosis of patients with atypical DBA when both ADA activity and RP gene tests show normal results. In our previous study, we demonstrated that GSH was a novel biomarker of DBA(Utsugisawa et al 2016;Ichimura et al 2017;Noguchi et al 2017;Sonoda et al 2018). Hence, the…”

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confidence: 98%

Enzymatic Changes in Red Blood Cells of Diamond-Blackfan Anemia

Utsugisawa

Uchiyama

Toki

et al. 2021

Tohoku J. Exp. Med.

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Diamond-Blackfan anemia is a congenital bone marrow failure syndrome characterized by red blood cell (RBC) aplasia with varied malformations in infants. Elevated activity of adenosine deaminase (ADA) has been considered as a useful biomarker of Diamond-Blackfan anemia, and ADA assay has been shown to be more sensitive than genetic diagnosis. Approximately, 80% of the examined patients showed elevated ADA activity, whereas genetic tests of ribosome subunit genes identified mutations in approximately 60% of the patients. We previously reported that reduced glutathione (GSH) levels in RBCs may serve as a biomarker of Diamond-Blackfan anemia. In this study, to confirm the universality of our data, we extended the analysis to seven RBC enzymes and GSH of 14 patients with Diamond-Blackfan anemia and performed a cross-analysis study using enzyme activity assay and recently reported proteome data. Statistical analysis revealed that both data exhibited high similarity, upregulation in the hexokinase and pentosephosphate pathway, and downregulation in glycolytic enzymes such as phosphofructokinase and pyruvate kinase, in the RBCs obtained from the subjects with Diamond-Blackfan anemia. The only discrepancy between enzyme activity and proteome data was observed in glucose-6-phosphate dehydrogenase (G6PD), as increased G6PD activity showed no relation with the significant elevation in protein levels. These results suggest that our enzymatic activity data of Diamond-Blackfan anemia are universal and that the enzymatic activation of G6PD via a hitherto-unveiled mechanism is another metabolic feature of RBCs of Diamond-Blackfan anemia.

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Atypical erythroblastosis in a patient with Diamond–Blackfan anemia who developed del(20q) myelodysplasia

Cited by 6 publications

References 23 publications

Mutations in the zebrafish hmgcs1 gene reveal a novel function for isoprenoids during red blood cell development

Mutations in the zebrafish hmgcs1 gene reveal a novel function for isoprenoids during red blood cell development

Mutations in the zebrafishhmgcs1gene reveal a novel function for isoprenoids during red blood cell development

Enzymatic Changes in Red Blood Cells of Diamond-Blackfan Anemia

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