Megakaryocytes from <i>CYCS</i> mutation‐associated thrombocytopenia release platelets by both proplatelet‐dependent and ‐independent processes

Ong, Lily; Morison, Ian M.; Ledgerwood, Elizabeth C.

doi:10.1111/bjh.14421

Cited by 27 publications

(30 citation statements)

References 32 publications

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“…The physical and biochemical properties of the G41S, G41A and G41T variants have been extensively studied. 25, 60–64 All three variants show increased peroxidase activity 61 that correlates with the stability of the heme crevice as measured by the accessibility of the alkaline conformer and the strength of the heme-Met80 bond. 62 However, introduction of the G41S mutation into mouse Cyt c shows that the correlation between a more accessible alkaline state and higher peroxidase activity is not absolute, 61 consistent with our results for K72A Hu Cyt c .…”

Section: Discussionmentioning

confidence: 97%

Effect of a K72A Mutation on the Structure, Stability, Dynamics, and Peroxidase Activity of Human Cytochrome c

et al. 2017

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We test the hypothesis that Lys72 suppresses the intrinsic peroxidase activity of human cytochrome c, as observed previously for yeast iso-1-cytochrome c [McClelland et al. PNAS 111, 6648–6653 (2014)]. A 1.25 Å X-ray structure of K72A human cytochrome c shows that the mutation minimally affects structure. Guanidine hydrochloride denaturation demonstrates that the K72A mutation increases global stability by 0.5 kcal/mol. The K72A mutation also increases the apparent pKa of the alkaline transition, a measure of the stability of the heme crevice, by 0.5 units. Consistent with the increase in the apparent pKa, the rate of formation of the dominant alkaline conformer decreases and this conformer is no longer stabilized by proline isomerization. Peroxidase activity measurements show that the K72A mutation increases kcat by 1.6– to 4–fold at pH values from 7 to 10, a larger effect than for the yeast protein. X-ray structures of wild type and K72A human cytochrome c indicate that direct interactions of Lys72 with the far side of Ω-loop D, which are seen in X-ray structures of horse and yeast cytochrome c and could suppress peroxidase activity, are lacking. Instead, we propose that the larger effect of the K72A mutation on peroxidase activity of human versus yeast cytochrome c results from relief of steric interactions between the side chains at positions 72 and 81 (Ile in human versus Ala in yeast), which suppress the dynamics of Ω-loop D necessary for the intrinsic peroxidase activity of cytochrome c.

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Section: Discussionmentioning

confidence: 97%

Effect of a K72A Mutation on the Structure, Stability, Dynamics, and Peroxidase Activity of Human Cytochrome c

et al. 2017

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“…According to the clinical information of the patients in our study and previous studies, CYCS ‐based thrombocytopenia presents a consistent phenotype. All four families showed low platelet counts (4/4, 100%), while the other complete blood count results were all normal (4/4, 100%) . One family (1/4, 25%) showed bleeding tendency with platelet aggregation defect (Table ).…”

Section: Discussionmentioning

confidence: 96%

“…1 To date, only three families with CYCS missense variants have been reported: a large New Zealander family (p.Gly42Ser), an Italian family (p.Tyr49His), and a white/mixed British family (p.Ala52Val). [2][3][4][5] These patients were affected by an autosomal dominant phenotype characterized by low platelet count without extra hematological findings. Moreover, these patients' peripheral blood cell morphologies, including platelet size, were all normal.…”

Section: Funding Informationmentioning

confidence: 99%

“…Cytochrome c is an electron carrier in the mitochondrial respiratory chain as well as a key initiator of apoptosis . To date, only three families with CYCS missense variants have been reported: a large New Zealander family (p.Gly42Ser), an Italian family (p.Tyr49His), and a white/mixed British family (p.Ala52Val) . These patients were affected by an autosomal dominant phenotype characterized by low platelet count without extra hematological findings.…”

Section: Introductionmentioning

confidence: 99%

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A novel CYCS mutation in the α‐helix of the CYCS C‐terminal domain causes non‐syndromic thrombocytopenia

et al. 2018

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We report a patient with thrombocytopenia from a Japanese family with hemophilia A spanning four generations. Various etiologies of thrombocytopenia, including genetic, immunological, and hematopoietic abnormalities, determine the prognosis for this disease. In this study, we identified a novel heterozygous mutation in a gene encoding cytochrome c, somatic (CYCS, MIM123970) using whole exome sequencing. This variant (c.301_303del:p.Lys101del) is located in the α-helix of the cytochrome c (CYCS) C-terminal domain. In silico structural analysis suggested that this mutation results in protein folding instability. CYCS is one of the key factors regulating the intrinsic apoptotic pathway and the mitochondrial respiratory chain. Using the yeast model system, we clearly demonstrated that this one amino acid deletion (in-frame) resulted in significantly reduced cytochrome c protein expression and functional defects in the mitochondrial respiratory chain, indicating that the loss of function of cytochrome c underlies thrombocytopenia. The clinical features of known CYCS variants have been reported to be confined to mild or asymptomatic thrombocytopenia, as was observed for the patient in our study. This study clearly demonstrates that thrombocytopenia can result from CYCS loss-of-function variants.

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“…In addition, many of the genes targeted only by HXMMT but not by CXC were related to circulation and blood coagulation. For instance, CYCS was shown to be involved in blood platelet formation and regulatory processes [21,22]. APOD, a crucial component of lipoproteins that transports lipids and stabilizes the structure of lipoproteins, was found to also be closely related to angiogenesis, a critical pathophysiological process in PDR [23].…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology-based Approach to Comparatively Predict the Active Ingredients and Molecular Targets of Compound Xueshuantong Capsule and Hexuemingmu Tablet in the Treatment of Proliferative Diabetic Retinopathy

Yao

Xin

Zhan

et al. 2020

Preprint

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Background Compound Xueshuantong capsule (CXC) and Hexuemingmu tablet (HXMMT) are two important Chinese patent medicines (CPMs) frequently used to treat proliferative diabetic retinopathy (PDR), especially when complicated with vitreous hemorrhage (VH). However, a network pharmacology approach to understand the therapeutic mechanisms of these two CPMs in PDR has not been applied. The aim of the study was to identify differences in active ingredients between CXC and HXMMT and to comparatively predict and further analyze the molecular targets shared by these CPMs and PDR. Materials and methods The differentially expressed messenger RNAs (mRNAs) between normal retinal tissues in healthy individuals and active fibrovascular membranes in PDR patients were retrieved from the Gene Expression Omnibus database. The active ingredients of CXC and HXMMT and the targets of these ingredients were retrieved from the Traditional Chinese Medicine Systems Pharmacology database. The intersections of the CPM (CXC and HXMMT) targets and PDR targets were determined. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed, and the ingredient-target networks, protein-protein interaction networks and KEGG-target (KEGG-T) networks were constructed. Results There CXC contains 4 herbal drugs in CXC, and HXMMT contains 19. Radix salviae is the only herbal drug common to both. CXC had 34 potential therapeutic targets in PDR, while HXMMT had these 34 and 10 additional targets. Both CPMs shared the following main processes: response to reactive oxygen species and oxidative stress, regulation of blood vessel diameter and size, vasoconstriction, smooth muscle contraction, hemostasis and blood coagulation. The shared pathways included the AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, relaxin signaling pathway, IL-17 signaling pathway, etc. Conclusions Both CXC and HXMMT include components effective in treating PDR. Radix salviae, the only herbal drug common to both CPMs, contains many useful active ingredients. HXMMT has more therapeutic targets shared by different active ingredients and more abundant gene functions than CXC. Moreover, the AGE-RAGE signaling pathway in diabetic complications was the most significantly enriched pathway in both networks. However, these findings should be verified through further research.

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Megakaryocytes from CYCS mutation‐associated thrombocytopenia release platelets by both proplatelet‐dependent and ‐independent processes

Cited by 27 publications

References 32 publications

Effect of a K72A Mutation on the Structure, Stability, Dynamics, and Peroxidase Activity of Human Cytochrome c

Effect of a K72A Mutation on the Structure, Stability, Dynamics, and Peroxidase Activity of Human Cytochrome c

A novel CYCS mutation in the α‐helix of the CYCS C‐terminal domain causes non‐syndromic thrombocytopenia

Network Pharmacology-based Approach to Comparatively Predict the Active Ingredients and Molecular Targets of Compound Xueshuantong Capsule and Hexuemingmu Tablet in the Treatment of Proliferative Diabetic Retinopathy

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