A mutation in the iron-responsive element of &lt;i&gt;ALAS2&lt;/i&gt; is a modifier of disease severity in a patient suffering from &lt;i&gt;CLPX&lt;/i&gt; associated erythropoietic protoporphyria

Ducamp, Sarah; Luscieti, Sara; Ferrer‐Cortès, Xènia; Nicolas, Gaël; Manceau, Hana; Peoc’h, Katell; Yien, Yvette Y.; Kannengiesser, Caroline; Gouya, Laurent; Puy, Hervé; Sánchez, Mayka

doi:10.3324/haematol.2020.272450

Cited by 19 publications

(16 citation statements)

References 15 publications

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“…Overall, our findings in a fixed genetic background group could support the hypothesis that the overexpression of ALAS2 mRNA in EPP patients likely contributes to the disease etiology and therefore is a potential target for developing new treatment options in EPP ( Ducamp et al, 2021 ; Halloy et al, 2021 ).…”

Section: Discussionsupporting

confidence: 78%

Heme Biosynthetic Gene Expression Analysis With dPCR in Erythropoietic Protoporphyria Patients

et al. 2022

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Background: The heme biosynthesis (HB) involves eight subsequent enzymatic steps. Erythropoietic protoporphyria (EPP) is caused by loss-of-function mutations in the ferrochelatase (FECH) gene, which in the last HB step inserts ferrous iron into protoporphyrin IX (PPIX) to form heme.Aim and method: The aim of this work was to for the first time analyze the mRNA expression of all HB genes in peripheral blood samples of patients with EPP having the same genotype FECH c.[215dupT]; [315-48T > C] as compared to healthy controls by highly sensitive and specific digital PCR assays (dPCR).Results: We confirmed a decreased FECH mRNA expression in patients with EPP. Further, we found increased ALAS2 and decreased ALAS1, CPOX, PPOX and HMBS mRNA expression in patients with EPP compared to healthy controls. ALAS2 correlated with FECH mRNA expression (EPP: r = 0.63, p = 0.03 and controls: r = 0.68, p = 0.02) and blood parameters like PPIX (EPP: r = 0.58 p = 0.06).Conclusion: Our method is the first that accurately quantifies HB mRNA from blood samples with potential applications in the monitoring of treatment effects of mRNA modifying therapies in vivo, or investigation of the HB pathway and its regulation. However, our findings should be studied in separated blood cell fractions and on the enzymatic level.

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Section: Discussionsupporting

confidence: 78%

Heme Biosynthetic Gene Expression Analysis With dPCR in Erythropoietic Protoporphyria Patients

et al. 2022

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“…Hence, cells have specific regulatory mechanisms that couple heme synthesis with utilization. This is observed in the diversity of phenotypes caused by disorders of heme synthesis, or in loss of function in model organisms ( Balwani and Desnick, 2012 ; Chen et al, 2019 ; Peoc’h et al, 2019 ; Poli et al, 2021 ; Chung et al, 2014 ; Hildick-Smith et al, 2013 ; Phillips et al, 2019 ; Wang et al, 2011 ; Yien et al, 2017 ; Troadec et al, 2011 ; Ducamp et al, 2021 ). Although defects in heme synthesis are often associated with hematologic diseases, loss of function studies and disease phenotypes make clear that many tissues and pathways depend on the correct regulation of heme synthesis for their function.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Heme Synthesis by Mitochondrial Homeostasis Proteins

Yien

Perfetto

2022

Front. Cell Dev. Biol.

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Heme plays a central role in diverse, life-essential processes that range from ubiquitous, housekeeping pathways such as respiration, to highly cell-specific ones such as oxygen transport by hemoglobin. The regulation of heme synthesis and its utilization is highly regulated and cell-specific. In this review, we have attempted to describe how the heme synthesis machinery is regulated by mitochondrial homeostasis as a means of coupling heme synthesis to its utilization and to the metabolic requirements of the cell. We have focused on discussing the regulation of mitochondrial heme synthesis enzymes by housekeeping proteins, transport of heme intermediates, and regulation of heme synthesis by macromolecular complex formation and mitochondrial metabolism. Recently discovered mechanisms are discussed in the context of the model organisms in which they were identified, while more established work is discussed in light of technological advancements.

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“…In addition, AHSP plays an important role in the physiological processes that regulate vascular carbon monoxide concentration [ 13 ]. ALAS2 is the first rate-limiting enzyme in the erythrocyte heme biosynthesis pathway [ 14 ] and may function as a modifier gene [ 15 ]. Its overexpression causes transgenic mice to exhibit muscle atrophy, which is associated with muscle mitochondrial dysfunction induced by ALA accumulation [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

A Bioinformatics Study of Ropivacaine plus Dexamethasone Prolonging the Duration of Nerve Block

Chen

et al. 2022

Computational Intelligence and Neuroscience

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The study focuses on the potential function of dexamethasone on ropivacaine in sciatic nerve blocks. Nine Sprague–Dawley (SD) rats were randomly divided into three groups: normal group (NG), control group (CG), and experimental group (EG), with three rats in each group. The CG was injected with diluted ropivacaine (0.5% concentration); the EG was injected with a diluted ropivacaine+dexamethasone mixture, and the NG was injected with an equal amount of saline. The sciatic nerve in the thigh was collected for sequencing two days after injection in each group. Differential analysis was performed for NG-vs-CG, NG-vs-EG, and CG-vs-EG based on the sequencing dataset. The modular genes associated with ropivacaine and ropivacaine+ dexamethasone were screened by weighted coexpression network analysis (WGCNA), differentially expressed modules among them were enriched for analysis, and protein-protein interaction (PPI) networks were constructed to observe high and low expression among key genes in immune cells. Twenty-two and three differential genes associated with ropivacaine (green-yellow module) and ropivacaine+dexamethasone (palevioletred3 module) were acquired, respectively, which played important roles in biological processes such as erythrocyte homeostasis, erythroid differentiation, and hemoglobin metabolic processes. PPI revealed that AHSP, ALAS2, EPB42, HBB, and SLC4A1 were interacting and the expression of these five genes was upregulated in the CG compared with the NG, while the expression of them was downregulated in the EG compared with the CG. The immunological analysis also showed significant differences in the expression of various immune cells in the 3 groups. AHSP, ALAS2, EPB42, HBB, and SLC4A1 are genes associated with hemoglobin, and dexamethasone combined with ropivacaine may prolong anesthesia by affecting local vasoconstriction to some extent.

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A mutation in the iron-responsive element of <i>ALAS2</i> is a modifier of disease severity in a patient suffering from <i>CLPX</i> associated erythropoietic protoporphyria

Abstract: Not available.

Cited by 19 publications

References 15 publications

Heme Biosynthetic Gene Expression Analysis With dPCR in Erythropoietic Protoporphyria Patients

Heme Biosynthetic Gene Expression Analysis With dPCR in Erythropoietic Protoporphyria Patients

Regulation of Heme Synthesis by Mitochondrial Homeostasis Proteins

A Bioinformatics Study of Ropivacaine plus Dexamethasone Prolonging the Duration of Nerve Block

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