Variants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility

Endo, Yukari; Groom, Linda; Çelik, Alper; Kraeva, Natalia; Lee, Chang Seok; Jung, Sung Yun; Gardner, Lois; Shaw, Marie‐Anne; Hamilton, Susan L.; Hopkins, Philip M.; Dirksen, Robert T.; Riazi, Sheila; Dowling, James J.

doi:10.1038/s41467-022-31088-8

Cited by 8 publications

(5 citation statements)

References 72 publications

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“…Zebrafish (6 dpf) obtained from heterozygous matings were placed in individual wells of a 48-well dish and swimming behavior was analyzed at the basal level. Caffeine (Millipore Sigma, C0750) and dantrolene (Millipore Sigma, D9175) treatments were performed as previously described with some modification ( Endo et al, 2022 ). E3 water was replaced with 0.5 μM caffeine-containing E3 water, and fish were incubated for 1 h. Subsequently, caffeine was replaced with normal E3 water.…”

Section: Methodsmentioning

confidence: 99%

Intrinsic and extrinsic regulation of rhabdomyolysis susceptibility by Tango2

Kim

Casey

Tao

et al. 2023

Disease Models &Amp; Mechanisms

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Rhabdomyolysis is a clinical emergency characterized by severe muscle damage, resulting in the release of intracellular muscle components, which leads to myoglobinuria and, in severe cases, acute kidney failure. Rhabdomyolysis is caused by genetic factors linked to increased disease susceptibility in response to extrinsic triggers. Recessive mutations in TANGO2 result in episodic rhabdomyolysis, metabolic crises, encephalopathy, and cardiac arrhythmia. The underlying mechanism contributing to disease onset in response to specific triggers remains unclear. To address these challenges, we created a zebrafish model of Tango2 deficiency. Here we demonstrate that the loss of Tango2 in zebrafish results in growth defects, early lethality, and increased susceptibility of skeletal muscle defects in response to extrinsic triggers similar to TANGO2 patients. Using lipidomics, we identified alterations in the glycerolipid pathway in tango2 mutants which is critical for membrane stability and energy balance. Therefore, these studies provide insight into key disease processes in Tango2 deficiency and have increased our understanding of the impacts of specific defects on predisposition to environmental triggers in TANGO2-related disorders.

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Section: Methodsmentioning

confidence: 99%

Intrinsic and extrinsic regulation of rhabdomyolysis susceptibility by Tango2

Kim

Casey

Tao

et al. 2023

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

show abstract

“…Zebrafish (6dpf) obtained from heterozygous mattings were placed in individual wells of a 48 well dish and swimming behavior was analyzed at the basal level. Caffeine and dantrolene treatment were performed as previously described with some modifications (Endo et al, 2022). Subsequently, E3 water was replaced with 0.5uM caffeine containing E3 water and fish were incubated for 1 hr and caffeine was replaced with normal E3 water.…”

Section: Methodsmentioning

confidence: 99%

Glycerolipid defects in skeletal muscle contribute to rhabdomyolysis in Tango2 deficiency

Casey

Kim

Tao

et al. 2022

Preprint

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Rhabdomyolysis is a clinical emergency characterized by severe muscle damage resulting in the release of intracellular muscle components leading to myoglobinuria and in severe cases, acute kidney failure. Rhabdomyolysis is caused by genetic factors that are linked to increased disease susceptibility in response to extrinsic triggers. Recessive mutations inTANGO2result in episodic rhabdomyolysis, metabolic crises, encephalopathy and cardiac arrhythmia, the underlying mechanism contributing to disease onset in response to specific triggers remains unclear. To address these challenges, we created a zebrafish model of Tango2 deficiency. Here we show that loss of Tango2 in zebrafish results in growth defects, early lethality and increased susceptibility of muscle defects similar toTANGO2patients. Detailed analyses of skeletal muscle revealed defects in the sarcoplasmic reticulum and mitochondria at the onset of disease development. The sarcoplasmic reticulum (SR) constitutes the primary lipid biosynthesis site and regulates calcium handling in skeletal muscle to control excitation-contraction coupling. Tango2 deficient SR exhibits increased sensitivity to calcium release that was partly restored by inhibition of Ryr1-mediated Ca2+release in skeletal muscle. Using lipidomics, we identified alterations in the glycerolipid state oftango2mutants which is critical for membrane stability and energy balance. Therefore, these studies provide insight into key disease processes in Tango2 deficiency and increased our understanding of how specific defects can predispose to environmental triggers in TANGO2-related disorders.

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“…Mutant gene loci are curated as alleles of genes and are part of a genotype together with the background strain when that information is provided. Zebrafish are also amenable to transgene insertion to knock out genes ( Amsterdam et al 2004 ), overexpress endogenous or other species genes ( Sabaawy et al 2006 ; Padanad et al 2012 ), insert mutant genes ( Kimelman et al 2017 ; Endo et al 2022 ), or express fluorescent proteins to mark anatomical structures ( Lawson and Weinstein 2002 ; Clark et al 2011 ). Transgene insertion is accomplished by the injection of DNA constructs (transgenic constructs) into zebrafish embryos, which are then raised to maturity and screened for stable germline transmission ( Stuart et al 1990 ; Culp et al 1991 ).…”

Section: Zfin Annotation Componentsmentioning

confidence: 99%

From multiallele fish to nonstandard environments, how ZFIN assigns phenotypes, human disease models, and gene expression annotations to genes

et al. 2023

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Danio rerio is a model organism used to investigate vertebrate development. Manipulation of the zebrafish genome and resultant gene products by mutation or targeted knockdown has made the zebrafish a good system for investigating gene function, providing a resource to investigate genetic contributors to phenotype and human disease. Phenotypic outcomes can be the result of gene mutation, targeted knockdown of gene products, manipulation of experimental conditions, or any combination thereof. Zebrafish have been used in various genetic and chemical screens to identify genetic and environmental contributors to phenotype and disease outcomes. The Zebrafish Information Network (ZFIN, zfin.org) is the central repository for genetic, genomic, and phenotypic data that result from research using Danio rerio. Here we describe how ZFIN annotates phenotype, expression, and disease model data across various experimental designs, how we computationally determine wild-type gene expression, the phenotypic gene, and how these results allow us to propagate gene expression, phenotype, and disease model data to the correct gene, or gene related entity.

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Variants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility

Cited by 8 publications

References 72 publications

Intrinsic and extrinsic regulation of rhabdomyolysis susceptibility by Tango2

Intrinsic and extrinsic regulation of rhabdomyolysis susceptibility by Tango2

Glycerolipid defects in skeletal muscle contribute to rhabdomyolysis in Tango2 deficiency

From multiallele fish to nonstandard environments, how ZFIN assigns phenotypes, human disease models, and gene expression annotations to genes

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