Journal articles: 'CASQ1'

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Sun, Zhipeng, Luqi Wang, Lu Han, Yue Wang, Yuan Zhou, Qiang Li, Yongquan Wu, et al. "Functional Calsequestrin-1 Is Expressed in the Heart and Its Deficiency Is Causally Related to Malignant Hyperthermia-Like Arrhythmia." Circulation 144, no. 10 (September 7, 2021): 788–804. http://dx.doi.org/10.1161/circulationaha.121.053255.

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Background: Calsequestrins (Casqs), comprising the Casq1 and Casq2 isoforms, buffer Ca 2+ and regulate its release in the sarcoplasmic reticulum of skeletal and cardiac muscle, respectively. Human inherited diseases associated with mutations in CASQ1 or CASQ2 include malignant hyperthermia/environmental heat stroke (MH/EHS) and catecholaminergic polymorphic ventricular tachycardia. However, patients with an MH/EHS event often experience arrhythmia for which the underlying mechanism remains unknown. Methods: Working hearts from conventional ( Casq1 -KO) and cardiac-specific ( Casq1 -CKO) Casq1 knockout mice were monitored in vivo and ex vivo by ECG and electric mapping, respectively. MH was induced by 2% isoflurane and treated intraperitoneally with dantrolene. Time-lapse imaging was used to monitor intracellular Ca 2+ activity in isolated mouse cardiomyocytes or neonatal rat ventricular myocytes with knockdown, overexpression, or truncation of the Casq1 gene. Conformational change in both Casqs was determined by cross-linking Western blot analysis. Results: Like patients with MH/EHS, Casq1 -KO and Casq1 -CKO mice had faster basal heart rate and ventricular tachycardia on exposure to 2% isoflurane, which could be relieved by dantrolene. Basal sinus tachycardia and ventricular ectopic electric triggering also occurred in Casq1 -KO hearts ex vivo. Accordingly, the ventricular cardiomyocytes from Casq1 -CKO mice displayed dantrolene-sensitive increased Ca 2+ waves and diastole premature Ca 2+ transients/oscillations on isoflurane. Neonatal rat ventricular myocytes with Casq1-knockdown had enhanced spontaneous Ca 2+ sparks/transients on isoflurane, whereas cells overexpressing Casq1 exhibited decreased Ca 2+ sparks/transients that were absent in cells with truncation of 9 amino acids at the C terminus of Casq1. Structural evaluation showed that most of the Casq1 protein was present as a polymer and physically interacted with ryanodine receptor-2 in the ventricular sarcoplasmic reticulum. The Casq1 isoform was also expressed in human myocardium. Mechanistically, exposure to 2% isoflurane or heating at 41 °C induced Casq1 oligomerization in mouse ventricular and skeletal muscle tissues, leading to a reduced Casq1/ryanodine receptor-2 interaction and increased ryanodine receptor-2 activity in the ventricle. Conclusions: Casq1 is expressed in the heart, where it regulates sarcoplasmic reticulum Ca 2+ release and heart rate. Casq1 deficiency independently causes MH/EHS-like ventricular arrhythmia by trigger-induced Casq1 oligomerization and a relief of its inhibitory effect on ryanodine receptor-2–mediated Ca 2+ release, thus revealing a new inherited arrhythmia and a novel mechanism for MH/EHS arrhythmogenesis.

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Paolini, Cecilia, Marco Quarta, Marco Dainese, Mirta Tomasi, Marta Canato, Alessandra Nori, Bjorn C. Knollmann, Paul D. Allen, Carlo Reggiani, and Feliciano Protasi. "Initial Characterization of CASQ1/CASQ2 Knockout (double CASQ-Null) Mice." Biophysical Journal 98, no. 3 (January 2010): 546a—547a. http://dx.doi.org/10.1016/j.bpj.2009.12.2963.

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Woo, Jin Seok, Seung Yeon Jeong, Ji Hee Park, Jun Hee Choi, and Eun Hui Lee. "Calsequestrin: a well-known but curious protein in skeletal muscle." Experimental & Molecular Medicine 52, no. 12 (December 2020): 1908–25. http://dx.doi.org/10.1038/s12276-020-00535-1.

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AbstractCalsequestrin (CASQ) was discovered in rabbit skeletal muscle tissues in 1971 and has been considered simply a passive Ca2+-buffering protein in the sarcoplasmic reticulum (SR) that provides Ca2+ ions for various Ca2+ signals. For the past three decades, physiologists, biochemists, and structural biologists have examined the roles of the skeletal muscle type of CASQ (CASQ1) in skeletal muscle and revealed that CASQ1 has various important functions as (1) a major Ca2+-buffering protein to maintain the SR with a suitable amount of Ca2+ at each moment, (2) a dynamic Ca2+ sensor in the SR that regulates Ca2+ release from the SR to the cytosol, (3) a structural regulator for the proper formation of terminal cisternae, (4) a reverse-directional regulator of extracellular Ca2+ entries, and (5) a cause of human skeletal muscle diseases. This review is focused on understanding these functions of CASQ1 in the physiological or pathophysiological status of skeletal muscle.

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Jeong, Seung Yeon, Mi Ri Oh, Jun Hee Choi, Jin Seok Woo, and Eun Hui Lee. "Calsequestrin 1 Is an Active Partner of Stromal Interaction Molecule 2 in Skeletal Muscle." Cells 10, no. 11 (October 20, 2021): 2821. http://dx.doi.org/10.3390/cells10112821.

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Calsequestrin 1 (CASQ1) in skeletal muscle buffers and senses Ca2+ in the sarcoplasmic reticulum (SR). CASQ1 also regulates store-operated Ca2+ entry (SOCE) by binding to stromal interaction molecule 1 (STIM1). Abnormal SOCE and/or abnormal expression or mutations in CASQ1, STIM1, or STIM2 are associated with human skeletal, cardiac, or smooth muscle diseases. However, the functional relevance of CASQ1 along with STIM2 has not been studied in any tissue, including skeletal muscle. First, in the present study, it was found by biochemical approaches that CASQ1 is bound to STIM2 via its 92 N-terminal amino acids (C1 region). Next, to examine the functional relevance of the CASQ1-STIM2 interaction in skeletal muscle, the full-length wild-type CASQ1 or the C1 region was expressed in mouse primary skeletal myotubes, and the myotubes were examined using single-myotube Ca2+ imaging experiments and transmission electron microscopy observations. The CASQ1-STIM2 interaction via the C1 region decreased SOCE, increased intracellular Ca2+ release for skeletal muscle contraction, and changed intracellular Ca2+ distributions (high Ca2+ in the SR and low Ca2+ in the cytosol were observed). Furthermore, the C1 region itself (which lacks Ca2+-buffering ability but has STIM2-binding ability) decreased the expression of Ca2+-related proteins (canonical-type transient receptor potential cation channel type 6 and calmodulin 1) and induced mitochondrial shape abnormalities. Therefore, in skeletal muscle, CASQ1 plays active roles in Ca2+ movement and distribution by interacting with STIM2 as well as Ca2+ sensing and buffering.

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Serano, Matteo, Laura Pietrangelo, Cecilia Paolini, Flavia A. Guarnier, and Feliciano Protasi. "Oxygen Consumption and Basal Metabolic Rate as Markers of Susceptibility to Malignant Hyperthermia and Heat Stroke." Cells 11, no. 16 (August 9, 2022): 2468. http://dx.doi.org/10.3390/cells11162468.

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Calsequestrin 1 (CASQ1) and Ryanodine receptor 1 (RYR1) are two of the main players in excitation–contraction (EC) coupling. CASQ1-knockout mice and mice carrying a mutation in RYR1 (Y522S) linked to human malignant hyperthermia susceptibility (MHS) both suffer lethal hypermetabolic episodes when exposed to halothane (MHS crises) and to environmental heat (heat stroke, HS). The phenotype of Y522S is more severe than that of CASQ1-null mice. As MHS and HS are hypermetabolic responses, we studied the metabolism of adult CASQ1-null and Y522S mice using wild-type (WT) mice as controls. We found that CASQ1-null and Y522S mice have increased food consumption and higher core temperature at rest. By indirect calorimetry, we then verified that CASQ1-null and Y522S mice show an increased oxygen consumption and a lower respiratory quotient (RQ). The accelerated metabolism of CASQ1-null and Y522S mice was also accompanied with a reduction in body fat. Moreover, both mouse models displayed increased oxygen consumption and a higher core temperature during heat stress. The results collected suggest that metabolic rate, oxygen consumption, and body temperature at rest, all more elevated in Y522S than in CASQ1-null mice, could possibly be used as predictors of the level of susceptibility to hyperthermic crises of mice (and possibly humans).

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Kraeva, Natalia, Elena Zvaritch, Wanda Frodis, Olga Sizova, Alexander Kraev, David H. MacLennan, and Sheila Riazi. "CASQ1 Gene Is an Unlikely Candidate for Malignant Hyperthermia Susceptibility in the North American Population." Anesthesiology 118, no. 2 (February 1, 2013): 344–49. http://dx.doi.org/10.1097/01.anes.0000530185.78660.da.

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Abstract Background Malignant hyperthermia (MH, MIM# 145600) is a complex pharmacogenetic disorder that is manifested in predisposed individuals as a potentially lethal reaction to volatile anesthetics and depolarizing muscle relaxants. Studies of CASQ1-null mice have shown that CASQ1, encoding calsequestrin 1, the major Ca2+ binding protein in the lumen of the sarcoplasmic reticulum, is a candidate gene for MH in mice. The aim of this study was to establish whether the CASQ1 gene is associated with MH in the North American population. Methods The entire coding region of CASQ1 in 75 unrelated patients diagnosed by caffeine-halothane contracture test as MH susceptible (MHS) was analyzed by DNA sequencing. Subsequently, three groups of unrelated individuals (130 MHS, 100 MH negative, and 192 normal controls) were genotyped for a variant that was identified by sequencing. Levels of CASQ1 expression in the muscle from unrelated MHS and MH negative individuals were estimated by Western blotting. Results Screening of the entire coding sequence of the CASQ1 gene in 75 MHS patients revealed a single variant c.260T > C (p.Met87Thr) in exon 1. This variant is unlikely to be pathogenic, because its allele frequency in the MHS group was not significantly different from that of controls. There was also no difference in calsequestrin 1 protein levels between muscle samples from MHS and controls, including those carrying the p.Met87Thr variant. Conclusions This study revealed a low level of protein coding sequence variability within the human CASQ1 gene, indicating that CASQ1 is not a major MHS locus in the North American population.

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Tomasi, Mirta, Marta Canato, Cecilia Paolini, Marco Dainese, Carlo Reggiani, Pompeo Volpe, Feliciano Protasi, and Alessandra Nori. "Calsequestrin (CASQ1) rescues function and structure of calcium release units in skeletal muscles of CASQ1-null mice." American Journal of Physiology-Cell Physiology 302, no. 3 (February 2012): C575—C586. http://dx.doi.org/10.1152/ajpcell.00119.2011.

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Amplitude of Ca2+ transients, ultrastructure of Ca2+ release units, and molecular composition of sarcoplasmic reticulum (SR) are altered in fast-twitch skeletal muscles of calsequestrin-1 (CASQ1)-null mice. To determine whether such changes are directly caused by CASQ1 ablation or are instead the result of adaptive mechanisms, here we assessed ability of CASQ1 in rescuing the null phenotype. In vivo reintroduction of CASQ1 was carried out by cDNA electro transfer in flexor digitorum brevis muscle of the mouse. Exogenous CASQ1 was found to be correctly targeted to the junctional SR (jSR), as judged by immunofluorescence and confocal microscopy; terminal cisternae (TC) lumen was filled with electron dense material and its width was significantly increased, as judged by electron microscopy; peak amplitude of Ca2+ transients was significantly increased compared with null muscle fibers transfected only with green fluorescent protein (control); and finally, transfected fibers were able to sustain cytosolic Ca2+ concentration during prolonged tetanic stimulation. Only the expression of TC proteins, such as calsequestrin 2, sarcalumenin, and triadin, was not rescued as judged by Western blot. Thus our results support the view that CASQ1 plays a key role in both Ca2+ homeostasis and TC structure.

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Semplicini, Claudio, Cinzia Bertolin, Luca Bello, Boris Pantic, Francesca Guidolin, Sara Vianello, Francesco Catapano, et al. "The clinical spectrum of CASQ1-related myopathy." Neurology 91, no. 17 (September 26, 2018): e1629-e1641. http://dx.doi.org/10.1212/wnl.0000000000006387.

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ObjectiveTo identify and characterize patients with calsequestrin 1 (CASQ1)–related myopathy.MethodsPatients selected according to histopathologic features underwent CASQ1 genetic screening. CASQ1-mutated patients were clinically evaluated and underwent muscle MRI. Vacuole morphology and vacuolated fiber type were characterized.ResultsTwenty-two CASQ1-mutated patients (12 families) were identified, 21 sharing the previously described founder mutation (p.Asp244Gly) and 1 with the p.Gly103Asp mutation. Patients usually presented in the sixth decade with exercise intolerance and myalgias and later developed mild to moderate, slowly progressive proximal weakness with quadriceps atrophy and scapular winging. Muscle MRI (n = 11) showed a recurrent fibrofatty substitution pattern. Three patients presented subclinical cardiac abnormalities. Muscle histopathology in patients with p.Asp244Gly showed vacuoles in type II fibers appearing empty in hematoxylin-eosin, Gomori, and nicotinamide adenine dinucleotide (NADH) tetrazolium reductase stains but strongly positive for sarcoplasmic reticulum proteins. The muscle histopathology of p.Gly103Asp mutation was different, showing also NADH-positive accumulation consistent with tubular aggregates.ConclusionsWe report the clinical and molecular details of the largest cohort of CASQ1-mutated patients. A possible heart involvement is presented, further expanding the phenotype of the disease. One mutation is common due to a founder effect, but other mutations are possible. Because of a paucity of symptoms, it is likely that CASQ1 mutations may remain undiagnosed if a muscle biopsy is not performed.

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Guarnier, Flávia Alessandra, Antonio Michelucci, Matteo Serano, Laura Pietrangelo, Claudia Pecorai, Simona Boncompagni, and Feliciano Protasi. "Aerobic Training Prevents Heatstrokes in Calsequestrin-1 Knockout Mice by Reducing Oxidative Stress." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–14. http://dx.doi.org/10.1155/2018/4652480.

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Calsequestrin-1 knockout (CASQ1-null) mice suffer lethal episodes when exposed to strenuous exercise and environmental heat, crises known as exertional/environmental heatstroke (EHS). We previously demonstrated that administration of exogenous antioxidants (N-acetylcysteine and trolox) reduces CASQ1-null mortality during exposure to heat. As aerobic training is known to boost endogenous antioxidant protection, we subjected CASQ1-null mice to treadmill running for 2 months at 60% of their maximal speed for 1 h, 5 times/week. When exposed to heat stress protocol (41°C/1 h), the mortality rate of CASQ1-null mice was significantly reduced compared to untrained animals (86% versus 16%). Protection from heatstrokes was accompanied by a reduced increase in core temperature during the stress protocol and by an increased threshold of response to caffeine of isolated extensor digitorum longus muscles during in vitro contracture test. At cellular and molecular levels, aerobic training (i) improved mitochondrial function while reducing their damage and (ii) lowered calpain activity and lipid peroxidation in membranes isolated from sarcoplasmic reticulum and mitochondria. Based on this evidence, we hypothesize that the protective effect of aerobic training is essentially mediated by a reduction in oxidative stress during exposure of CASQ1-null mice to adverse environmental conditions.

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Michelucci, Antonio, Cecilia Paolini, Marta Canato, Lan Wei-Lapierre, Laura Pietrangelo, Alessandro De Marco, Carlo Reggiani, Robert T. Dirksen, and Feliciano Protasi. "Antioxidants Protect Calsequestrin-1 Knockout Mice from Halothane- and Heat-induced Sudden Death." Anesthesiology 123, no. 3 (September 1, 2015): 603–17. http://dx.doi.org/10.1097/aln.0000000000000748.

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Abstract Background: Mice lacking calsequestrin-1 (CASQ1-null), a Ca2+-binding protein that modulates the activity of Ca2+ release in the skeletal muscle, exhibit lethal hypermetabolic episodes that resemble malignant hyperthermia in humans when exposed to halothane or heat stress. Methods: Because oxidative species may play a critical role in malignant hyperthermia crises, we treated CASQ1-null mice with two antioxidants, N-acetylcysteine (NAC, Sigma-Aldrich, Italy; provided ad libitum in drinking water) and (±)-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox, Sigma-Aldrich; administered by intraperitoneal injection), before exposure to halothane (2%, 1 h) or heat (41°C, 1 h). Results: NAC and Trolox significantly protected CASQ1-null mice from lethal episodes, with mortality being 79% (n = 14), 25% (n = 16), and 20% (n = 5) during halothane exposure and 86% (n = 21), 29% (n = 21), and 33% (n = 6) during heat stress in untreated, NAC-treated, and Trolox-treated mice, respectively. During heat challenge, an increase in core temperature in CASQ1-null mice (42.3° ± 0.1°C, n=10) was significantly reduced by both NAC and Trolox (40.6° ± 0.3°C, n = 6 and 40.5° ± 0.2°C, n = 6). NAC treatment of CASQ1-null muscles/mice normalized caffeine sensitivity during in vitro contracture tests, Ca2+ transients in single fibers, and significantly reduced the percentage of fibers undergoing rhabdomyolysis (37.6 ± 2.5%, 38/101 fibers in 3 mice; 11.6 ± 1.1%, 21/186 fibers in 5 mice). The protective effect of antioxidant treatment likely resulted from mitigation of oxidative stress, because NAC reduced mitochondrial superoxide production, superoxide dismutase type-1 expression, and 3-nitrotyrosine expression, and increased both reduced glutathione and reduced glutathione/oxidized glutathione ratio. Conclusion: These studies provide a deeper understanding of the mechanisms that underlie hyperthermic crises in CASQ1-deficient muscle and demonstrate that antioxidant pretreatment may prevent them.

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Sztretye, Monika, Jianxun Yi, Lourdes Figueroa, Jingsong Zhou, Leandro Royer, Paul Allen, Gustavo Brum, and Eduardo Ríos. "Measurement of RyR permeability reveals a role of calsequestrin in termination of SR Ca2+ release in skeletal muscle." Journal of General Physiology 138, no. 2 (July 25, 2011): 231–47. http://dx.doi.org/10.1085/jgp.201010592.

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The mechanisms that terminate Ca2+ release from the sarcoplasmic reticulum are not fully understood. D4cpv-Casq1 (Sztretye et al. 2011. J. Gen. Physiol. doi:10.1085/jgp.201010591) was used in mouse skeletal muscle cells under voltage clamp to measure free Ca2+ concentration inside the sarcoplasmic reticulum (SR), [Ca2+]SR, simultaneously with that in the cytosol, [Ca2+]c, during the response to long-lasting depolarization of the plasma membrane. The ratio of Ca2+ release flux (derived from [Ca2+]c(t)) over the gradient that drives it (essentially equal to [Ca2+]SR) provided directly, for the first time, a dynamic measure of the permeability to Ca2+ of the releasing SR membrane. During maximal depolarization, flux rapidly rises to a peak and then decays. Before 0.5 s, [Ca2+]SR stabilized at ∼35% of its resting level; depletion was therefore incomplete. By 0.4 s of depolarization, the measured permeability decayed to ∼10% of maximum, indicating ryanodine receptor channel closure. Inactivation of the t tubule voltage sensor was immeasurably small by this time and thus not a significant factor in channel closure. In cells of mice null for Casq1, permeability did not decrease in the same way, indicating that calsequestrin (Casq) is essential in the mechanism of channel closure and termination of Ca2+ release. The absence of this mechanism explains why the total amount of calcium releasable by depolarization is not greatly reduced in Casq-null muscle (Royer et al. 2010. J. Gen. Physiol. doi:10.1085/jgp.201010454). When the fast buffer BAPTA was introduced in the cytosol, release flux became more intense, and the SR emptied earlier. The consequent reduction in permeability accelerated as well, reaching comparable decay at earlier times but comparable levels of depletion. This observation indicates that [Ca2+]SR, sensed by Casq and transmitted to the channels presumably via connecting proteins, is determinant to cause the closure that terminates Ca2+ release.

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Paolini, Cecilia, Marco Quarta, Laura D'Onofrio, Carlo Reggiani, and Feliciano Protasi. "Differential Effect of Calsequestrin Ablation on Structure and Function of Fast and Slow Skeletal Muscle Fibers." Journal of Biomedicine and Biotechnology 2011 (2011): 1–10. http://dx.doi.org/10.1155/2011/634075.

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We compared structure and function of EDL and Soleus muscles in adult (4–6 m) mice lacking both Calsequestrin (CASQ) isoforms, the main SR Ca2+-binding proteins. Lack of CASQ induced ultrastructural alterations in ~30% of Soleus fibers, but not in EDL. Twitch time parameters were prolonged in both muscles, although tension was not reduced. However, when stimulated for 2 sec at 100 hz, Soleus was able to sustain contraction, while in EDL active tension declined by 70–80%. The results presented in this paper unmask a differential effect of CASQ1&2 ablation in fast versus slow fibers. CASQ is essential in EDL to provide large amount of Ca2+released from the SR during tetanic stimulation. In contrast, Soleus deals much better with lack of CASQ because slow fibers require lower Ca2+amounts and slower cycling to function properly. Nevertheless, Soleus suffers more severe structural damage, possibly because SR Ca2+leak is more pronounced.

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Dawes, Michelle, Trudy Moore-Harrison, Alicia T. Hamilton, Tyrone Ceaser, Kelli J. Kochan, Penny K. Riggs, and J. Timothy Lightfoot. "Differential Gene Expression in High- and Low-Active Inbred Mice." BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/361048.

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Numerous candidate genes have been suggested in the recent literature with proposed roles in regulation of voluntary physical activity, with little evidence of these genes’ functional roles. This study compared the haplotype structure and expression profile in skeletal muscle and brain of inherently high- (C57L/J) and low- (C3H/HeJ) active mice. Expression of nine candidate genes [Actn2,Actn3,Casq1,Drd2,Lepr,Mc4r,Mstn,Papss2, andGlut4(a.k.a.Slc2a4)] was evaluated via RT-qPCR. SNPs were observed in regions ofActn2,Casq1,Drd2,Lepr, andPapss2; however, no SNPs were located in coding sequences or associated with any known regulatory sequences. In mice exposed to a running wheel,Casq1(P=0.0003) andMstn(P=0.002) transcript levels in the soleus were higher in the low-active mice. However, when these genes were evaluated in naïve animals, differential expression was not observed, demonstrating a training effect. Among naïve mice, no genes in either tissue exhibited differential expression between strains. Considering that no obvious SNP mechanisms were determined or differential expression was observed, our results indicate that genomic structural variation or gene expression data alone is not adequate to establish any of these genes’ candidacy or causality in relation to regulation of physical activity.

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Böhm, J., X. Lornage, S. Zanotti, P. Cudia, C. Schneider-Gold, E. Malfatti, M. Mora, and J. Laporte. "CASQ1 mutations impair calsequestrin polymerization and cause tubular aggregate myopathy." Neuromuscular Disorders 27 (October 2017): S176. http://dx.doi.org/10.1016/j.nmd.2017.06.300.

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Li, Ying, Yu Wang, and Lin Ma. "An Association Study of CASQ1 Gene Polymorphisms and Heat Stroke." Genomics, Proteomics & Bioinformatics 12, no. 3 (June 2014): 127–32. http://dx.doi.org/10.1016/j.gpb.2014.03.004.

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Böhm, Johann, Xavière Lornage, Frederic Chevessier, Catherine Birck, Simona Zanotti, Paola Cudia, Monica Bulla, et al. "CASQ1 mutations impair calsequestrin polymerization and cause tubular aggregate myopathy." Acta Neuropathologica 135, no. 1 (October 16, 2017): 149–51. http://dx.doi.org/10.1007/s00401-017-1775-x.

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Sztretye, Monika, Jianxun Yi, Lourdes Figueroa, Jingsong Zhou, Leandro Royer, and Eduardo Ríos. "D4cpv-calsequestrin: a sensitive ratiometric biosensor accurately targeted to the calcium store of skeletal muscle." Journal of General Physiology 138, no. 2 (July 25, 2011): 211–29. http://dx.doi.org/10.1085/jgp.201010591.

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Current fluorescent monitors of free [Ca2+] in the sarcoplasmic reticulum (SR) of skeletal muscle cells are of limited quantitative value. They provide either a nonratio signal that is difficult to calibrate and is not specific or, in the case of Forster resonant energy transfer (FRET) biosensors, a signal of small dynamic range, which may be degraded further by imperfect targeting and interference from endogenous ligands of calsequestrin. We describe a novel tool that uses the cameleon D4cpv, which has a greater dynamic range and lower susceptibility to endogenous ligands than earlier cameleons. D4cpv was targeted to the SR by fusion with the cDNA of calsequestrin 1 or a variant that binds less Ca2+. “D4cpv-Casq1,” expressed in adult mouse at concentrations up to 22 µmole/liter of muscle cell, displayed the accurate targeting of calsequestrin and stayed inside cells after permeabilization of surface and t system membranes, which confirmed its strict targeting. FRET ratio changes of D4cpv-Casq1 were calibrated inside cells, with an effective KD of 222 µM and a dynamic range [(Rmax − Rmin)/Rmin] of 2.5, which are improvements over comparable sensors. Both the maximal ratio, Rmax, and its resting value were slightly lower in areas of high expression, a variation that was inversely correlated to distance from the sites of protein synthesis. The average [Ca2+]SR in 74 viable cells at rest was 416 µM. The distribution of individual ratio values was Gaussian, but that of the calculated [Ca2+]SR was skewed, with a tail of very large values, up to 6 mM. Model calculations reproduce this skewness as the consequence of quantifiably small variations in biosensor performance. Local variability, a perceived weakness of biosensors, thus becomes quantifiable. It is demonstrably small in D4cpv. D4cpv-Casq1 therefore provides substantial improvements in sensitivity, specificity, and reproducibility over existing monitors of SR free Ca2+ concentration.

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Michelucci, Antonio, Simona Boncompagni, Marta Canato, Carlo Reggiani, and Feliciano Protasi. "Estrogens Protect Calsequestrin-1 Knockout Mice from Lethal Hyperthermic Episodes by Reducing Oxidative Stress in Muscle." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–15. http://dx.doi.org/10.1155/2017/6936897.

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Oxidative stress has been proposed to play a key role in malignant hyperthermia (MH), a syndrome caused by excessive Ca2+release in skeletal muscle. Incidence of mortality in male calsequestrin-1 knockout (CASQ1-null) mice during exposure to halothane and heat (a syndrome closely resembling human MH) is far greater than that in females. To investigate the possible role of sex hormones in this still unexplained gender difference, we treated male and female CASQ1-null mice for 1 month, respectively, with Premarin (conjugated estrogens) and leuprolide (GnRH analog) and discovered that during exposure to halothane and heat Premarin reduced the mortality rate in males (79–27% and 86–20%), while leuprolide increased the incidence of mortality in females (18–73% and 24–82%). We then evaluated the (a) responsiveness of isolated muscles to temperature and caffeine, (b) sarcoplasmic reticulum (SR) Ca2+release in single fibers, and (c) oxidative stress and the expression levels of main enzymes involved in the regulation of the redox balance in muscle. Premarin treatment reduced the temperature and caffeine sensitivity of EDL muscles, normalized SR Ca2+release, and reduced oxidative stress in males, suggesting that female sex hormones may protect mice from lethal hyperthermic episodes by reducing both the SR Ca2+leak and oxidative stress.

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Böhm, Johann, and Jocelyn Laporte. "La myopathie à agrégats tubulaires et le syndrome de Stormorken." médecine/sciences 34 (November 2018): 26–31. http://dx.doi.org/10.1051/medsci/201834s208.

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Le calcium est un régulateur essentiel pour un grand nombre de fonctions cellulaires, et une perturbation de l’homéostasie calcique peut sévèrement troubler la physiologie de différents tissus. CASQ1, STIM1, et ORAI1 codent pour des facteurs clés contrôlant les flux de calcium, et des mutations de ces gènes sont à l’origine de la myopathie à agrégats tubulaires et du syndrome de Stormorken. Ces deux maladies forment un continuum clinique regroupant faiblesse musculaire, myosis, thrombopénie, hyposplénisme, ichthyose, dyslexie et petite taille.

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Knoll, A., A. Stratil, G. Reiner, L. J. Peelman, M. Van Poucke, and H. Geldermann. "Linkage and radiation hybrid mapping of the porcine calsequestrin 1 (CASQ1 ) gene to chromosome 4q." Animal Genetics 33, no. 5 (September 30, 2002): 390–92. http://dx.doi.org/10.1046/j.1365-2052.2002.00896_10.x.

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Nasirikalmarzi, Rasoul, Somayee Bodaghi, Azad Fatahirad, and fatemeh keshavarzi. "e Prevalence of Different Genotypes CASQ1 rs2275703 (A / C) in Patients with Type 2 Diabetes Mellitus." journal of ilam university of medical sciences 27, no. 6 (January 1, 2020): 96–105. http://dx.doi.org/10.29252/sjimu.27.6.96.

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Mueller, Nicolas J., Robert A. Wilkinson, and Jay A. Fishman. "Listeria monocytogenes Infection in Caspase-11-Deficient Mice." Infection and Immunity 70, no. 5 (May 2002): 2657–64. http://dx.doi.org/10.1128/iai.70.5.2657-2664.2002.

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ABSTRACT Caspase-11 (Cas11) is a cysteine protease involved in programmed cell death and cytokine maturation. Through activation of Cas1 (interleukin-1β [IL-1β]-converting enzyme), Cas11 is directly involved in the maturation of IL-1β and IL-18. Apoptosis is mediated through Cas3. Given the role of apoptosis and cytokine signaling during the innate immune response in intracellular infection, we examined Cas11-deficient (Cas11−/−) mice during infection with Listeria monocytogenes. Cas11−/− and wild-type C57BL/6 mice were equally susceptible to intravenous infection with L. monocytogenes, resulting in similar bacterial burdens in tissue and similar survival rates. By contrast, enhanced susceptibility was observed in control mice on a mixed genetic 129/C57BL/DBA2 background. Cas11−/− and wild-type mice infected with Listeria had similar hepatic microabscess formation in terms of histologic appearance, size, and number. Apoptosis of L. monocytogenes-infected hepatocytes in vivo and in vitro in primary culture was not altered by the absence of Cas11. Serum IL-18 and IL-1β levels were similar in Cas11−/− mice and controls. Endotoxin (lipopolysaccharide [LPS])-challenged Cas11−/− mice were deficient in the production of gamma interferon. IL-1β responses in Cas11−/− were normal with intravenous administration of LPS but decreased with intraperitoneal administration. Our findings suggest that Cas11 deficiency does not impair the immune response to infection with L. monocytogenes. Apoptosis and maturation of IL-18 and IL-1β were normal despite Cas11 deficiency. LPS-induced proinflammatory pathways are altered by the absence of Cas11. While Cas11-mediated Cas1 and Cas3 activation is crucial for cytokine maturation and apoptosis during inflammation, alternative pathways allow normal inflammatory and apoptotic responses during infection with L. monocytogenes.

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Lahooti, Hooshang. "Association of the CASQ1 Gene SNP rs3838216 with Graves’ Ophthalmopathy and Hashimoto’s Thyroiditis in Patients with Thyroid Autoimmunity." Ophthalmology Research: An International Journal 2, no. 6 (January 10, 2014): 281–93. http://dx.doi.org/10.9734/or/2014/10623.

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Das, S. K., W. Chu, Z. Zhang, S. J. Hasstedt, and S. C. Elbein. "Calsquestrin 1 (CASQ1) Gene Polymorphisms Under Chromosome 1q21 Linkage Peak Are Associated With Type 2 Diabetes in Northern European Caucasians." Diabetes 53, no. 12 (November 23, 2004): 3300–3306. http://dx.doi.org/10.2337/diabetes.53.12.3300.

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Fu, M., C. M. Damcott, M. Sabra, T. I. Pollin, S. H. Ott, J. Wang, M. J. Garant, J. R. O'Connell, B. D. Mitchell, and A. R. Shuldiner. "Polymorphism in the Calsequestrin 1 (CASQ1) Gene on Chromosome 1q21 Is Associated With Type 2 Diabetes in the Old Order Amish." Diabetes 53, no. 12 (November 23, 2004): 3292–99. http://dx.doi.org/10.2337/diabetes.53.12.3292.

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Michelucci, Antonio, Alessandro De Marco, Laura Pietrangelo, Cecilia Paolini, Susan L. Hamilton, and Feliciano Protasi. "Lethal Exertional Strokes in RYR1Y522S/WT and CASQ1-Null Mice are Prevented by Drugs used to Treat Malignant Hyperthermia in Humans." Biophysical Journal 106, no. 2 (January 2014): 124a. http://dx.doi.org/10.1016/j.bpj.2013.11.737.

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Sztretye, Monika, Jianxun Yi, Leandro Royer, Jingsong Zhou, Björn Knollmann, Paul D. Allen, Feliciano Protasi, and Eduardo Ríos. "D4cpv-Casq1. A Novel Approach for Targeting Biosensors Yields Detailed Dynamic Imaging of Calcium Concentration Inside the Sarcoplasmic Reticulum of Living Cells." Biophysical Journal 98, no. 3 (January 2010): 294a—295a. http://dx.doi.org/10.1016/j.bpj.2009.12.1604.

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Bal, Naresh C., Nivedita Jena, Danesh Sopariwala, Tuniki Balaraju, Sana Shaikh, Chandralata Bal, Ashoke Sharon, Sandor Gyorke, and Muthu Periasamy. "Probing cationic selectivity of cardiac calsequestrin and its CPVT mutants." Biochemical Journal 435, no. 2 (March 29, 2011): 391–99. http://dx.doi.org/10.1042/bj20101771.

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CASQ (calsequestrin) is a Ca2+-buffering protein localized in the muscle SR (sarcoplasmic reticulum); however, it is unknown whether Ca2+ binding to CASQ2 is due to its location inside the SR rich in Ca2+ or due to its preference for Ca2+ over other ions. Therefore a major aim of the present study was to determine how CASQ2 selects Ca2+ over other metal ions by studying monomer folding and subsequent aggregation upon exposure to alkali (monovalent), alkaline earth (divalent) and transition (polyvalent) metals. We additionally investigated how CPVT (catecholaminergic polymorphic ventricular tachycardia) mutations affect CASQ2 structure and its molecular behaviour when exposed to different metal ions. Our results show that alkali and alkaline earth metals can initiate similar molecular compaction (folding), but only Ca2+ can promote CASQ2 to aggregate, suggesting that CASQ2 has a preferential binding to Ca2+ over all other metals. We additionally found that transition metals (having higher co-ordinated bonding ability than Ca2+) can also initiate folding and promote aggregation of CASQ2. These studies led us to suggest that folding and formation of higher-order structures depends on cationic properties such as co-ordinate bonding ability and ionic radius. Among the CPVT mutants studied, the L167H mutation disrupts the Ca2+-dependent folding and, when folding is achieved by Mn2+, L167H can undergo aggregation in a Ca2+-dependent manner. Interestingly, domain III mutants (D307H and P308L) lost their selectivity to Ca2+ and could be aggregated in the presence of Mg2+. In conclusion, these studies suggest that CPVT mutations modify CASQ2 behaviour, including folding, aggregation/polymerization and selectivity towards Ca2+.

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Hadrevi, J., M. F. Barbe, N. Ørtenblad, U. Frandsen, E. Boyle, S. Lazar, G. Sjøgaard, and K. Søgaard. "Calcium Fluxes in Work-Related Muscle Disorder: Implications from a Rat Model." BioMed Research International 2019 (September 30, 2019): 1–14. http://dx.doi.org/10.1155/2019/5040818.

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Introduction. Ca2+ regulatory excitation-contraction coupling properties are key topics of interest in the development of work-related muscle myalgia and may constitute an underlying cause of muscle pain and loss of force generating capacity. Method. A well-established rat model of high repetition high force (HRHF) work was used to investigate if such exposure leads to an increase in cytosolic Ca2+ concentration ([Ca2+]i) and changes in sarcoplasmic reticulum (SR) vesicle Ca2+ uptake and release rates. Result. Six weeks exposure of rats to HRHF increased indicators of fatigue, pain behaviors, and [Ca2+]i, the latter implied by around 50–100% increases in pCam, as well as in the Ca2+ handling proteins RyR1 and Casq1 accompanied by an ∼10% increased SR Ca2+ uptake rate in extensor and flexor muscles compared to those of control rats. This demonstrated a work-related altered myocellular Ca2+ regulation, SR Ca2+ handling, and SR protein expression. Discussion. These disturbances may mirror intracellular changes in early stages of human work-related myalgic muscle. Increased uptake of Ca2+ into the SR may reflect an early adaptation to avoid a sustained detrimental increase in [Ca2+]i similar to the previous findings of deteriorated Ca2+ regulation and impaired function in fatigued human muscle.

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Lee, Jun-Hoe, Kevin M. Lewis, Timothy W. Moural, Bogdan Kirilenko, Barbara Borgonovo, Gisa Prange, Manfred Koessl, Stefan Huggenberger, ChulHee Kang, and Michael Hiller. "Molecular parallelism in fast-twitch muscle proteins in echolocating mammals." Science Advances 4, no. 9 (September 2018): eaat9660. http://dx.doi.org/10.1126/sciadv.aat9660.

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Detecting associations between genomic changes and phenotypic differences is fundamental to understanding how phenotypes evolved. By systematically screening for parallel amino acid substitutions, we detected known as well as novel cases (Strc, Tecta, and Cabp2) of parallelism between echolocating bats and toothed whales in proteins that could contribute to high-frequency hearing adaptations. Our screen also showed that echolocating mammals exhibit an unusually high number of parallel substitutions in fast-twitch muscle fiber proteins. Both echolocating bats and toothed whales produce an extremely rapid call rate when homing in on their prey, which was shown in bats to be powered by specialized superfast muscles. We show that these genes with parallel substitutions (Casq1, Atp2a1, Myh2, and Myl1) are expressed in the superfast sound-producing muscle of bats. Furthermore, we found that the calcium storage protein calsequestrin 1 of the little brown bat and the bottlenose dolphin functionally converged in its ability to form calcium-sequestering polymers at lower calcium concentrations, which may contribute to rapid calcium transients required for superfast muscle physiology. The proteins that our genomic screen detected could be involved in the convergent evolution of vocalization in echolocating mammals by potentially contributing to both rapid Ca2+ transients and increased shortening velocities in superfast muscles.

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Sparsø, Thomas, Meena Shaheen Hussain, Knut Borch-Johnsen, Torben Jørgensen, Sten Madsbad, Torben Hansen, Oluf Pedersen, and Gitte Andersen. "Studies of association of the CASQ1 rs2275703 polymorphism in relation to type 2 diabetes and related quantitative metabolic traits among 7088 Danish whites." Molecular Genetics and Metabolism 92, no. 3 (November 2007): 278–82. http://dx.doi.org/10.1016/j.ymgme.2007.06.011.

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Chen, Haiyan, Giorgia Valle, Sandra Furlan, Alma Nani, Sandor Gyorke, Michael Fill, and Pompeo Volpe. "Mechanism of calsequestrin regulation of single cardiac ryanodine receptor in normal and pathological conditions." Journal of General Physiology 142, no. 2 (July 15, 2013): 127–36. http://dx.doi.org/10.1085/jgp.201311022.

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Release of Ca2+ from the sarcoplasmic reticulum (SR) drives contractile function of cardiac myocytes. Luminal Ca2+ regulation of SR Ca2+ release is fundamental not only in physiology but also in physiopathology because abnormal luminal Ca2+ regulation is known to lead to arrhythmias, catecholaminergic polymorphic ventricular tachycardia (CPVT), and/or sudden cardiac arrest, as inferred from animal model studies. Luminal Ca2+ regulates ryanodine receptor (RyR)2-mediated SR Ca2+ release through mechanisms localized inside the SR; one of these involves luminal Ca2+ interacting with calsequestrin (CASQ), triadin, and/or junctin to regulate RyR2 function. CASQ2-RyR2 regulation was examined at the single RyR2 channel level. Single RyR2s were incorporated into planar lipid bilayers by the fusion of native SR vesicles isolated from either wild-type (WT), CASQ2 knockout (KO), or R33Q-CASQ2 knock-in (KI) mice. KO and KI mice have CPVT-like phenotypes. We show that CASQ2(WT) action on RyR2 function (either activation or inhibition) was strongly influenced by the presence of cytosolic MgATP. Function of the reconstituted CASQ2(WT)–RyR2 complex was unaffected by changes in luminal free [Ca2+] (from 0.1 to 1 mM). The inhibition exerted by CASQ2(WT) association with the RyR2 determined a reduction in cytosolic Ca2+ activation sensitivity. RyR2s from KO mice were significantly more sensitive to cytosolic Ca2+ activation and had significantly longer mean open times than RyR2s from WT mice. Sensitivity of RyR2s from KI mice was in between that of RyR2 channels from KO and WT mice. Enhanced cytosolic RyR2 Ca2+ sensitivity and longer RyR2 open times likely explain the CPVT-like phenotype of both KO and KI mice.

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Semplicini, C., C. Bertolin, B. Pantic, L. Bello, S. Vianello, F. Catapano, I. Colombo, et al. "The blurred scenario of the new Calcium-related myopathies: clinical, radiological and molecular characterization of CASQ1 , STIM1 and ORAI1 myopathies diagnosed in Padova neuromuscular center." Neuromuscular Disorders 27 (October 2017): S97. http://dx.doi.org/10.1016/j.nmd.2017.06.024.

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Blottner, Dieter, Manuela Moriggi, Gabor Trautmann, Maria Hastermann, Daniele Capitanio, Enrica Torretta, Katharina Block, et al. "Space Omics and Tissue Response in Astronaut Skeletal Muscle after Short and Long Duration Missions." International Journal of Molecular Sciences 24, no. 4 (February 17, 2023): 4095. http://dx.doi.org/10.3390/ijms24044095.

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The molecular mechanisms of skeletal muscle adaptation to spaceflight are as yet not fully investigated and well understood. The MUSCLE BIOPSY study analyzed pre and postflight deep calf muscle biopsies (m. soleus) obtained from five male International Space Station (ISS) astronauts. Moderate rates of myofiber atrophy were found in long-duration mission (LDM) astronauts (~180 days in space) performing routine inflight exercise as countermeasure (CM) compared to a short-duration mission (SDM) astronaut (11 days in space, little or no inflight CM) for reference control. Conventional H&E scout histology showed enlarged intramuscular connective tissue gaps between myofiber groups in LDM post vs. preflight. Immunoexpression signals of extracellular matrix (ECM) molecules, collagen 4 and 6, COL4 and 6, and perlecan were reduced while matrix-metalloproteinase, MMP2, biomarker remained unchanged in LDM post vs. preflight suggesting connective tissue remodeling. Large scale proteomics (space omics) identified two canonical protein pathways associated to muscle weakness (necroptosis, GP6 signaling/COL6) in SDM and four key pathways (Fatty acid β-oxidation, integrin-linked kinase ILK, Rho A GTPase RHO, dilated cardiomyopathy signaling) explicitly in LDM. The levels of structural ECM organization proteins COL6A1/A3, fibrillin 1, FBN1, and lumican, LUM, increased in postflight SDM vs. LDM. Proteins from tricarboxylic acid, TCA cycle, mitochondrial respiratory chain, and lipid metabolism mostly recovered in LDM vs. SDM. High levels of calcium signaling proteins, ryanodine receptor 1, RyR1, calsequestrin 1/2, CASQ1/2, annexin A2, ANXA2, and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA1) pump, ATP2A, were signatures of SDM, and decreased levels of oxidative stress peroxiredoxin 1, PRDX1, thioredoxin-dependent peroxide reductase, PRDX3, or superoxide dismutase [Mn] 2, SOD2, signatures of LDM postflight. Results help to better understand the spatiotemporal molecular adaptation of skeletal muscle and provide a large scale database of skeletal muscle from human spaceflight for the better design of effective CM protocols in future human deep space exploration.

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Cavdarli, Sumeyye, Philippe Delannoy, and Sophie Groux-Degroote. "O-acetylated Gangliosides as Targets for Cancer Immunotherapy." Cells 9, no. 3 (March 17, 2020): 741. http://dx.doi.org/10.3390/cells9030741.

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O-acetylation of sialic acid residues is one of the main modifications of gangliosides, and modulates ganglioside functions. O-acetylation of gangliosides is dependent on sialyl-O-acetyltransferases and sialyl-O-acetyl-esterase activities. CAS1 Domain-Containing Protein 1 (CASD1) is the only human sialyl-O-acetyltransferases (SOAT) described until now. O-acetylated ganglioside species are mainly expressed during embryonic development and in the central nervous system in healthy adults, but are re-expressed during cancer development and are considered as markers of cancers of neuroectodermal origin. However, the specific biological roles of O-acetylated gangliosides in developing and malignant tissues have not been extensively studied, mostly because of the requirement of specific approaches and tools for sample preparation and analysis. In this review, we summarize our current knowledge of ganglioside biosynthesis and expression in normal and pathological conditions, of ganglioside O-acetylation analysis and expression in cancers, and of the possible use of O-acetylated gangliosides as targets for cancer immunotherapy.

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Luo, Huarong, Chengdang Xu, Bujun Ge, and Tianru Wang. "CASC1 Expression in Bladder Cancer Is Regulated by Exosomal miRNA-150: A Comprehensive Pan-Cancer and Bioinformatics Study." Computational and Mathematical Methods in Medicine 2022 (July 5, 2022): 1–18. http://dx.doi.org/10.1155/2022/8100325.

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This study explored the role of cancer susceptibility 1 (CASC1) in tumorigenesis and development as well as the key pathways affecting bladder cancer progression. CASC1 was examined in various normal tissues in humans using the HPA database to quantify its expression level and subcellular localization. CASC1 is abundantly expressed in tumor tissues, primarily in cytoplasmic vesicles and stroma. TIMER2 was used to analyze the correlation between CASC1 expression levels and the types of infiltrates associated with immune cells and immunosuppressive cells. MDSC, Treg, M2, and CAF were significantly correlated with CASC1 expression in various tumors. Comparing patients with and without CASC1 mutation, those with CASC1 mutation had worse overall survival, progression-free survival, and disease-free survival. The correlation between has-miR-150 and CASC1 (for the case of bladder cancer) was then analyzed, and the related ceRNA network was mapped. A negative relationship between CASC1 expression and has-miR-150 expression was found in cases of bladder cancer. And the presence of miR-150-targeted CASC1 may be associated with bladder cancer progression. CASC1 is expressed at elevated levels in various tumor tissues, and it is associated with tumorigenesis and development. Exosomes containing miR-150-targeted CASC1 may affect the progression of bladder cancer.

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Lacey, Carolyn, and Jerod A. Skyberg. "Inflammasomes promote the initiation of Brucella induced arthritis in an IL-18 dependent manner and mediate Brucella clearance independently of IFN-γ." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 64.4. http://dx.doi.org/10.4049/jimmunol.198.supp.64.4.

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Abstract Brucellosis, caused by the intracellular bacterial pathogen Brucella, is a zoonotic disease for which infection of the joints is the most common focal complication in humans. The purpose of this study was to identify if Brucella activation of inflammasomes and in turn caspase1/11 activation is responsible for inducing arthritis. Here we report caspase-1/11−/− (casp1/11−/−) mice had reduced swelling, inflammation and inflammatory cytokine levels early in infection relative to wild-type “WT” mice. Later in infection, joint inflammation was similar between WT and casp1/11−/− mice, but bacterial loads and swelling were greater in casp1/11−/− joints. While IL-1Rdeficiency reduced joint swelling, this effect occurred later and was not of the same magnitude as casp1/11 deficiency, indicating an IL-1 independent role of casp1/11. Casp1/11 induced inflammation was partially dependent on IL-18, and IFN-γ levels were reduced in both casp1/11−/− and IL-18-deficient mice relative to WT mice early in infection. However, while IFN-γ and casp1/11 both played a role in controlling joint Brucella burdens, an additive effect of these deficiencies was observed indicating that the protective effects of IFN-γ and casp1/11 on bacterial clearance are not interdependent. Enhanced arthritis and musculoskeletal inflammation was observed in IFN-γ-deficient, relative to WT mice. However, neutralization of IFN-γ in casp1/11−/− mice did not result in enhanced inflammation. Collectively these data demonstrate casp1/11 induces early inflammation in an IL-18 dependent manner. Moreover, there is an IFN-γ independent role of casp1/11 in joint Brucella clearance, and casp1/11 is responsible for enhanced inflammation observed in IFN-γ-deficient mice.

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Kannan, Venkatesan, Michael Massam, Stephen Cronin, and Parameswaran Nallappan. "Case1: Sinister Neck Swelling." Acta Paediatrica 95, no. 6 (June 1, 2006): 756–57. http://dx.doi.org/10.1080/08035250600575412.

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Kannan, Venkatesan, Michael Massam, Stephen Cronin, and Parameswaran Nallappan. "Case1: Sinister Neck Swelling." Acta Paediatrica 95, no. 6 (January 2, 2007): 756–57. http://dx.doi.org/10.1111/j.1651-2227.2006.tb02330.x.

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Ng, Kevin, Erron W. Titus, Krystien V. Lieve, Thomas M. Roston, Andrea Mazzanti, Frederick H. Deiter, Isabelle Denjoy, et al. "An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2 -Catecholaminergic Polymorphic Ventricular Tachycardia." Circulation 142, no. 10 (September 8, 2020): 932–47. http://dx.doi.org/10.1161/circulationaha.120.045723.

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Background: Genetic variants in calsequestrin-2 ( CASQ2 ) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2 -CPVT was sought through an international multicenter collaboration. Methods: Genotype-phenotype segregation in CASQ2 -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure. Results: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6–11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3–8.0; P =0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6–269.1; P <0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers. Conclusions: This international multicenter study of CASQ2 -CPVT redefines its heritability and confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.

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Kalyanasundaram, Anuradha, Serge Viatchenko-Karpinski, Andriy E. Belevych, Veronique A. Lacombe, Hyun Seok Hwang, Björn C. Knollmann, Sandor Gyorke, and Muthu Periasamy. "Functional consequences of stably expressing a mutant calsequestrin (CASQ2D307H) in the CASQ2 null background." American Journal of Physiology-Heart and Circulatory Physiology 302, no. 1 (January 2012): H253—H261. http://dx.doi.org/10.1152/ajpheart.00578.2011.

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The role of calsequestrin (CASQ2) in cardiac sarcoplasmic reticulum (SR) calcium (Ca2+) transport has gained significant attention since point mutations in CASQ2 were reported to cause ventricular arrhythmia. In the present study, we have critically evaluated the functional consequences of expressing the CASQ2D307H mutant protein in the CASQ2 null mouse. We recently reported that the mutant CASQ2D307H protein can be stably expressed in CASQ2 null hearts, and it targets appropriately to the junctional SR (Kalyanasundaram A, Bal NC, Franzini-Armstrong C, Knollmann BC, Periasamy M. J Biol Chem 285: 3076–3083, 2010). In this study, we found that introduction of CASQ2D307H protein in the CASQ2 null background partially restored triadin 1 levels, which were decreased in the CASQ2 null mice. Despite twofold expression (relative to wild-type CASQ2), the mutant protein failed to increase SR Ca2+ load. We also found that the Ca2+ transient decays slower in the CASQ2 null and CASQ2D307H cells. CASQ2D307H myocytes, when rhythmically paced and challenged with isoproterenol, exhibit spontaneous Ca2+ waves similar to CASQ2 null myocytes; however, the stability of Ca2+ cycling was increased in the CASQ2D307H myocytes. In the presence of isoproterenol, Ca2+-transient amplitude in CASQ2D307H myocytes was significantly decreased, possibly indicating an inherent defect in Ca2+ buffering capacity and release from the mutant CASQ2 at high Ca2+ concentrations. We also observed polymorphic ventricular tachycardia in the CASQ2D307H mice, although lesser than in the CASQ2 null mice. These data suggest that CASQ2D307H point mutation may affect Ca2+ buffering capacity and Ca2+ release. We propose that poor interaction between CASQ2D307H and triadin 1 could affect ryanodine receptor 2 stability, thereby increasing susceptibility to delayed afterdepolarizations and triggered arrhythmic activity.

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Pandiyan, Pushpa, Natarajan Bhaskaran, Carol J. Thiele, and Aaron Weinberg. "Identification of a role for Casz1 in the control of T helper differentiation and inflammation." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 223.4. http://dx.doi.org/10.4049/jimmunol.198.supp.223.4.

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Abstract While T helper (Th) cells constitute a critical arm of adaptive immune system and are important for host defense, unregulated expansion and imbalance in Th effector subsets contribute to inflammatory disorders. Here we show that Casz1, whose function is previously unknown in CD4+ T cells, determines the balance between various Th subsets. As systemic knockout mice are embryonically lethal, we generated conditional CD4 Casz1 knockout mice. Conditional deletion of Casz1 in CD4+ T cells significantly inhibits Th17 cell differentiation, but promotes Th1 differentiation. Loss of Casz1 in CD4+ T cells lowers susceptibility to experimental autoimmune encephalomyelitis, consistent with the reduced frequency of Th17 cells, despite an increase in Th1 cells. These results underscore the critical role of Casz1 in determining Th17 lineage differentiation in vivo. Transcriptome analyses of Casz1 deficient CD4+ T cells show a signature consistent with defective Th17 differentiation but enhanced Th1 differentiation. Taken together, these data reveal Casz1 as a new T helper cell regulator having important clinical implications for autoimmune inflammation.

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Zha, Weifeng, Bo Guo, Shuyue Chen, Junwei Lu, and Yunyun Shan. "MicroRNA-126-5p Regulates Proliferation and Apoptosis of IL-22-Stimulated Human Keratinocytes Through Regulating Caspase 1." Journal of Biomaterials and Tissue Engineering 11, no. 5 (May 1, 2021): 1010–16. http://dx.doi.org/10.1166/jbt.2021.2656.

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Objective: The study was aimed to explore the roles of miR-126-5p in psoriasis and the underlying molecular mechanisms. Methods: In vitro cell model of psoriasis was established by IL-22 induction. CASP1, the target gene of miR-126-5p, was predicted by TargetScan and verified through the dual luciferase reporter gene system. qRT-PCR was used to measure the mRNA expression of miR-126-5p and CASP1 in IL-22 stimulated HaCaT cells. The protein expression of CASP1, cleaved-caspase3 and caspase3 were measured by Western blot analysis. MTT assay and flow cytometry analysis were performed to detect the cell proliferation and apoptosis. A Caspase3 Activity Assay kit was used to detect the activity of Caspase3. Results: miR-126-5p was high expressed in IL-22 stimulated HaCaT cells compared with normal HaCaT cells. We predicted and verified that CASP1 was a direct target of miR-126-5p, and the mRNA and protein expression of CASP1 were reduced in IL-22 stimulated HaCaT cells compared with the normal HaCaT cells. miR-126-5p inhibitor and CASP1-siRNA significantly decreased the expression of miR-126-5p and CASP1 in HaCaT cells respectively. miR-126-5p inhibitor up-regulated the expression of CASP1 in HaCaT cells, and the effect was reversed by the transfection with CASP1-siRNA. In comparison with the control group, miR-126-5p inhibitor decreased the cell proliferation, induced apoptosis, and improved the activity of Caspase3, enhanced cleaved-caspase3/caspase3 ratio in IL-22 stimulated HaCaT cells, and all the effects were reversed by down-regulating CASP1. Conclusion: We demonstrated that miR-126-5p inhibitor played a protective role in psoriasis by targeting CASP1, evidenced by inhibiting IL-22-induced HaCaT cell proliferation and inducing apoptosis.

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Cavdarli, Sumeyye, Larissa Schröter, Malena Albers, Anna-Maria Baumann, Dorothée Vicogne, Jean-Marc Le Doussal, Martina Mühlenhoff, Philippe Delannoy, and Sophie Groux-Degroote. "Role of Sialyl-O-Acetyltransferase CASD1 on GD2 Ganglioside O-Acetylation in Breast Cancer Cells." Cells 10, no. 6 (June 11, 2021): 1468. http://dx.doi.org/10.3390/cells10061468.

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The O-acetylated form of GD2, almost exclusively expressed in cancerous tissues, is considered to be a promising therapeutic target for neuroectoderm-derived tumors, especially for breast cancer. Our recent data have shown that 9-O-acetylated GD2 (9-OAcGD2) is the major O-acetylated ganglioside species in breast cancer cells. In 2015, Baumann et al. proposed that Cas 1 domain containing 1 (CASD1), which is the only known human sialyl-O-acetyltransferase, plays a role in GD3 O-acetylation. However, the mechanisms of ganglioside O-acetylation remain poorly understood. The aim of this study was to determine the involvement of CASD1 in GD2 O-acetylation in breast cancer. The role of CASD1 in OAcGD2 synthesis was first demonstrated using wild type CHO and CHOΔCasd1 cells as cellular models. Overexpression using plasmid transfection and siRNA strategies was used to modulate CASD1 expression in SUM159PT breast cancer cell line. Our results showed that OAcGD2 expression was reduced in SUM159PT that was transiently depleted for CASD1 expression. Additionally, OAcGD2 expression was increased in SUM159PT cells transiently overexpressing CASD1. The modulation of CASD1 expression using transient transfection strategies provided interesting insights into the role of CASD1 in OAcGD2 and OAcGD3 biosynthesis, and it highlights the importance of further studies on O-acetylation mechanisms.

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Bakiu, Rigers. "Unfolded Protein Response and Triad Formation in Skeletal Muscles of Catecholaminergic Polymorphic Ventricular Tachycardia Mouse / Odgovor Razvijenog Proteina I Formiranje Trijada U Skeletnim Mišićima Miševa Sa Kateholaminergičkom Polimorfnom Ventrikularnom Tahikardijom." Acta Facultatis Medicae Naissensis 31, no. 4 (December 1, 2014): 225–31. http://dx.doi.org/10.2478/afmnai-2014-0028.

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Summary Isoform 2 of calsequestrin (CASQ2) is the main calcium-binding protein of sarcoplasmic reticulum (SR), expressed both in cardiac and in skeletal muscles. CASQ2 acts as an SR calcium (Ca2+) sensor and regulates SR Ca2+ release via interactions with triadin, junctin, and the ryanodine receptor. Various mutations of the csq2 gene lead to altered Ca2+ release and contractile dysfunction contributing to the development of arrhythmias and sudden cardiac death in young individuals affected by catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, a transgenic mouse carrying one of the identified CASQ2 point-mutations (R33Q) associated to CPVT was developed and a drastic reduction of the mutated protein was observed. Following a biomolecular approach, several analysis were performed using different antibody treatments in order to identify when the reduction of CASQ2 begins in skeletal muscles, unveil the mechanism involved in the reduction of CASQ2 in slow-twitch and fast twitch muscles and verify if other proteins are affected by the presence of the mutated protein. Mutated CASQ2 decreased soon after birth. Up-regulation of proteins associated to the unfolded protein response (UPR) was also observed. Important proteins in skeletal muscle triads formation were analyzed and increased protein levels were observed in adult knock-in CASQ2-R33Q/R33Q mice. Probably, R33Q mutation induced the decrease of CASQ2 by activation of the UPR and subsequently degradation through proteasome.

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Faggioni, Michela, and Björn C. Knollmann. "Calsequestrin 2 and arrhythmias." American Journal of Physiology-Heart and Circulatory Physiology 302, no. 6 (March 15, 2012): H1250—H1260. http://dx.doi.org/10.1152/ajpheart.00779.2011.

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Calsequestrin is the most abundant Ca-binding protein of the specialized endoplasmic reticulum found in muscle, the sarcoplasmic reticulum (SR). Calsequestrin binds Ca with high capacity and low affinity and importantly contributes to the mobilization of Ca during each contraction both in skeletal and cardiac muscle. Surprisingly, mutations in the gene encoding the cardiac isoform of calsequestrin (Casq2) have been associated with an inherited form of ventricular arrhythmia triggered by emotional or physical stress termed catecholaminergic polymorphic ventricular tachycardia (CPVT). Despite normal cardiac contractility and normal resting ECG, CPVT patients present with a high risk of sudden death at a young age. Here, we review recent new insights regarding the role of calsequestrin in genetic and acquired arrhythmia disorders. Mouse models of CPVT have shed light on the pathophysiological mechanism underlying CPVT. Casq2 is not only a Ca-storing protein as initially hypothesized, but it has a far more complex function in Ca handling and regulating SR Ca release channels. The functional importance of Casq2 interactions with other SR proteins and the importance of alterations in Casq2 trafficking are also being investigated. Reports of altered Casq2 trafficking in animal models of acquired heart diseases such as heart failure suggest that Casq2 may contribute to arrhythmia risk beyond genetic forms of Casq2 dysfunction.

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Dang, Wan-Tai, Dan Xu, Wen-Guang Xie, and Jing-Guo Zhou. "Expression of Caspase-1 Gene Transcript Variant mRNA in Peripheral Blood Mononuclear Cells of Patients with Primary Gout in Different TCM Syndromes." Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/361607.

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A large number of studies have shown that cysteinyl aspartate specific protease-1 (CASP1) played an important role in the inflammatory response of primary gout, but the decreased expression of different CASP1 transcript variant could inhibit the activation of IL-1β. Our study mainly analyzed the expression level and function of CASP1 gene transcript variant mRNA in peripheral blood mononuclear cells of patients with gout in different TCM syndromes. The expression of CASP1 gene transcript variant and IL-1βmRNA in PBMCs were detected in patients with PG [acute phase (AP: 44 cases); nonacute phase (NAP: 52 cases)] and healthy controls (HC: 30 cases) by reverse transcription-polymerase chain reaction and/or real-time quantitative polymerase chain reaction. The expressions of plasma IL-1βin patients with PG and HC were detected by enzyme-linked immunosorbent assay. Dysregulated expression of the CASP1 gene and its transcript variant, plasma proinflammatory cytokines in all patients with primary gout in different TCM syndromes, correlation analysis showed that there was negative correlation between the expression of CASP1-gamma gene transcript variant mRNA and IL-1βprotein in APPG group. The study suggested that CASP1 gene and its transcript variant may play a critical role in the inflammatory response of patients with PG in different phases and TCM syndromes.

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Valle, Giorgia, Michael Arad, and Pompeo Volpe. "Molecular adaptation to calsequestrin 2 (CASQ2) point mutations leading to catecholaminergic polymorphic ventricular tachycardia (CPVT): comparative analysis of R33Q and D307H mutants." Journal of Muscle Research and Cell Motility 41, no. 2-3 (September 2020): 251–58. http://dx.doi.org/10.1007/s10974-020-09587-2.

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AbstractHomozygous calsequestrin 2 (CASQ2) point mutations leads to catecholaminergic polymorphic ventricular tachycardia: a common pathogenetic feature appears to be the drastic reduction of mutant CASQ2 in spite of normal transcription. Comparative biochemical analysis of R33Q and D307H knock in mutant mice identifies different pathogenetic mechanisms for CASQ2 degradation and different molecular adaptive mechanisms. In particular, each CASQ2 point mutation evokes specific adaptive cellular and molecular processes in each of the four adaptive pathways investigated. Thus, similar clinical phenotypes and identical cellular mechanism for cardiac arrhythmia might imply different molecular adaptive mechanisms.

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Kim, Bohyun, Minsun Jung, and Kyung Chul Moon. "The Prognostic Significance of Protein Expression of CASZ1 in Clear Cell Renal Cell Carcinoma." Disease Markers 2019 (August 6, 2019): 1–6. http://dx.doi.org/10.1155/2019/1342161.

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Backgrounds. Clear cell renal cell carcinoma (ccRCC) is the most common histologic subtype of renal cell carcinoma (RCC) and shows a relatively poor prognosis among RCCs. Castor zinc finger 1 (CASZ1) is a transcription factor, prominently known for its tumor suppression role in neuroblastoma and other cancers. However, there has been no research about the prognostic significance of CASZ1 in ccRCC. In this study, we investigated CASZ1 expression in ccRCC and analyzed its prognostic implications. Methods. A total of 896 ccRCC patients, who underwent surgical resection from 1995 to 2008, were included. We prepared tissue microarray blocks, evaluated CASZ1 nuclear expression by immunohistochemistry, and classified the cases into low or high expression categories. Results. A low expression of CASZ1 was observed in 320 cases (35.7%) and was significantly associated with large tumor size, high World Health Organization/International Society of Urological Pathology (WHO/ISUP) grade, and high T category and M category. In survival analysis, a low expression of CASZ1 was significantly correlated with unfavorable progression-free survival (PFS) (p<0.001), overall survival (OS) (p<0.001), and cancer-specific survival (CSS) (p<0.001) and was an independent prognostic factor for PFS and CSS in multivariate analysis adjusted for tumor size, WHO/ISUP grade, T category, N category, and M category. Conclusions. Our study is the first to show the prognostic significance of CASZ1 expression in ccRCC. Our results revealed that low expression of CASZ1 is associated with poor prognosis and may serve as a new prognostic indicator.

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Wleklinski, Matthew, Shan Parikh, and Bjorn C. Knollmann. "Autosomal-dominant CASQ2-K180R Causes CPVT by a Different Mechanism than Autosomal-recessive Casq2 Mutations." Biophysical Journal 118, no. 3 (February 2020): 101a. http://dx.doi.org/10.1016/j.bpj.2019.11.709.

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Journal articles on the topic 'CASQ1'

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