The SDHB Arg230His mutation causing familial paraganglioma alters glycolysis in a new Caenorhabditis elegans model
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ABSTRACT:
PROVIDER: PRJNA666675 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12748963_1.fastq.gz | Fastqsanger.gz | |||
| SRR12748963_2.fastq.gz | Fastqsanger.gz | |||
| SRR12748964_1.fastq.gz | Fastqsanger.gz | |||
| SRR12748964_2.fastq.gz | Fastqsanger.gz | |||
| SRR12748965_1.fastq.gz | Fastqsanger.gz |
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Project description:The conserved B-subunit of succinate dehydrogenase (SDH) participates in the TCA cycle and mitochondrial electron transport. The Arg230His mutation in SDHB causes heritable pheochromocytoma/paraganglioma (PPGL). In C. elegans, we generated an in vivo PPGL model (SDHB-1 Arg244His; equivalent to human Arg230His) which manifests delayed development, shortened lifespan, attenuated ATP production and reduced mitochondrial number. Although succinate is elevated in both missense and null sdhb-1(gk165) mutants, transcriptomic comparison suggests very different causal mechanisms that are supported by metabolic analysis where only Arg244His (not null) worms elevate lactate/pyruvate levels, pointing to a missense-induced, ‘Warburg’-like aberrant glycolysis. In silico predictions of the SDHA-B dimer structure demonstrate that Arg230His modifies the catalytic cleft despite the latter’s remoteness from the mutation site. We hypothesise that Arg230His SDHB mutation rewires metabolism, reminiscent of metabolic reprogramming in cancer. Our tractable model provides a novel tool to investigate the metastatic propensity of this familial cancer and our approach may illuminate wider SDH pathology.
2020-10-01 | GSE158836 | GEO
Project description:The conserved B-subunit of succinate dehydrogenase (SDH) participates in the tricarboxylic acid cycle (TCA) cycle and mitochondrial electron transport. The Arg230His mutation in SDHB causes heritable pheochromocytoma/paraganglioma (PPGL). In Caenorhabditiselegans, we generated an in vivo PPGL model (SDHB-1 Arg244His; equivalent to human Arg230His), which manifests delayed development, shortened lifespan, attenuated ATP production and reduced mitochondrial number. Although succinate is elevated in both missense and null sdhb-1(gk165) mutants, transcriptomic comparison suggests very different causal mechanisms that are supported by metabolic analysis, whereby only Arg244His (not null) worms demonstrate elevated lactate/pyruvate levels, pointing to a missense-induced, Warburg-like aberrant glycolysis. In silico predictions of the SDHA-B dimer structure demonstrate that Arg230His modifies the catalytic cleft despite the latter's remoteness from the mutation site. We hypothesize that the Arg230His SDHB mutation rewires metabolism, reminiscent of metabolic reprogramming in cancer. Our tractable model provides a novel tool to investigate the metastatic propensity of this familial cancer and our approach could illuminate wider SDH pathology.This article has an associated First Person interview with the first author of the paper.
| S-EPMC7578352 | biostudies-literature
Project description:The pheochromocytomas are an important cause of secondary hypertension. Although pheochromocytoma susceptibility may be associated with germline mutations in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RET, the genetic basis for most cases of nonsyndromic familial pheochromocytoma is unknown. Recently, pheochromocytoma susceptibility has been associated with germline SDHD mutations. Germline SDHD mutations were originally described in hereditary paraganglioma, a dominantly inherited disorder characterized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane. Although mutations in SDHC and in SDHD may cause hereditary paraganglioma, germline SDHA mutations are associated with juvenile encephalopathy, and the phenotypic consequences of SDHB mutations have not been defined. To investigate the genetic causes of pheochromocytoma, we analyzed SDHB and SDHC, in familial and in sporadic cases. Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma. These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.
| S-EPMC1226047 | biostudies-literature
Project description:Effect of SDHB silencing using siRNA methodologies in the tumor phenotype We used microarrays to detail the global programme of gene expression when SDHB is silenced. Keywords: siRNA experiment (loss of function)
2008-04-01 | GSE10289 | GEO
Project description:Until now, it is nearly impossible to diagnose malignancy of peochormocytoma/paraganglioma with pathological examinations. The aim of the study is to find the genes which can be applied as a biomarker in the clinic to distinguish benign and malignant forms of pheochromocytoma/paraganglioma.
2014-08-17 | GSE60458 | GEO
Project description:Effect of SDHB silencing using siRNA methodologies in the tumor phenotype; We used microarrays to detail the global programme of gene expression when SDHB is silenced. Experiment Overall Design: Human hepatocellular carcinoma cell line Hep3B was stably silenced with control or SDHB-specific siRNAs. <br><br>This experiment was re-loaded into ArrayExpress in November 2010 after manual curation.
2008-06-11 | E-GEOD-10289 | biostudies-arrayexpress
Project description:Transcriptional analysis of one primary paraganglioma.
2020-06-15 | GSE123344 | GEO
Project description:Introduction: Genotype constitutes a pivotal factor in the comprehensive management of pheochromocytomas and paragangliomas (PPGLs). This underlines the need to (1) further elucidate the genetic etiology of these pathologies, (2) investigate the underlying pathogenic mechanisms, and (3) identify therapeutic targets. These goals rely on generating and studying relevant biological models, particularly in vivo. However, this has remained a disappointment using traditional animal models. In this context, there is a need to develop fast, reliable in vivo models of PPGLs which display clinically relevant biochemical hallmarks of PPGLs. Objective: Our study aims to establish zebrafish larvae as a relevant and convenient proxy for the functional characterization of PPGL-associated genetic variants. Methods: We took advantage of the genetic accessibility of zebrafish embryos to generate first-generation (F0) loss-of-function models for sdhb, a canonical PPGL-associated gene, using CRISPR/CAS9 technology. F0 zebrafish embryos were microinjected with a CRISPR/CAS9 molecular cocktail containing sdhb-specific guide RNAs and compared with control embryos injected with non-active CRISPR/CAS9. The mutagenic score of our CRISPR/CAS9 approach was validated by High-Resolution Melting analysis, and mutant zebrafish larvae were phenotyped during their first five days of development. Notably, the levels of catecholamines/metanephrines (in whole fish extract and bathing medium) and Krebs cycle metabolites were assessed by liquid chromatography-mass spectrometry. Other relevant phenotypic readouts were also performed, such as heart rate, swimming activity and overall survival. To validate the specificity of our findings, we also analyzed other zebrafish genetic mutants diseased controls (i.e. nf1 CRISPants as PPGL positive controls and scn1a-mutant as non-PPGL negative genetic controls). Finally, we performed an RNA-sequencing assay from sdhb-CRISPant and controls larvae. Results: Sdhb CRISPants exhibit increased heart rates, reduced swimming activity and premature death. In whole fish extracts, normetanephrine (NM), metanephrine (MN), and dopamine (DA) levels were about three times higher in sdhb CRISPants than in control larvae. In the bathing medium, NM and MN were also significantly elevated, along with 3-MT. We confirmed the specificity of our findings by showing that nf1-mutant larvae exhibit similar catecholamine levels but also show an adrenergic phenotype typical of cluster 2 variants of PPGLs. In contrast, scn1a-mutant larvae, despite suffering from severe epileptic encephalopathy associated with reduced lifespan, did not display elevated catecholamine levels. Complementary metabolic profiling showed that sdhb CRISPants depict a clear Complex II dysfunction signature, characterized by elevated succinate, lactate, NAD+, along with reduced aspartate and glutamate levels. Additionally, RNA-sequencing revealed downregulation of sdhb and fads2, and upregulation of genes involved in the hypoxia response, angiogenesis, stress response, and glycolysis in sdhb CRISPants compared to Cas9-control larvae. Conclusion: In this work, we validated the relevance of F0 loss-of-function zebrafish models (CRISPant) to study the pathogenicity of PPGL-causing genetic variants in vivo. We present the first in vivo model of sdhb loss-of-function with oversecretion of free catecholamines, a key clinical hallmark of PPGLs in humans. We also show that other pathological molecular hallmarks are found increased such as Krebs cycle metabolites and relevant phenotypic readouts (tachycardia, reduced lifespan, and consistent transcriptomic dysregulations). These findings suggest that zebrafish is a relevant physiopathologic model for studying PPGLs and their associated genetic etiologies and opens the door for streamlining preclinical precision medicine approaches for PPGLs.
2025-08-20 | GSE300914 | GEO
Project description:Until now, it is nearly impossible to diagnose malignancy of pheochromocytoma/paraganglioma with pathological examinations. The aim of the study is to find the genes which can be applied as a biomarker in the clinic to distinguish benign and malignant forms of pheochromocytoma/paraganglioma.
2014-08-17 | GSE60457 | GEO
Project description:Our study found that low SDHB expression and high succinate levels are important for maintaining embryo implantation in the first trimester; therefore, high SDHB expression and low succinate levels during early pregnancy may increase the risk of RSA. To investigate why villous SDHB expression increases pathologically in RSA but exhibits dynamically low levels during the first trimester followed by high levels under physiological conditions, we detected CpG site methylation levels in the SDHB promoter region of villi from both individuals with RSA and controls.
2021-04-13 | GSE171877 | GEO