The function and regulation of calsequestrin-2: implications in calcium-mediated arrhythmias

Sibbles, Elliot T.; Waddell, H.; Mereacre, Valeria; Jones, Peter P.; Munro, Michelle L.

doi:10.1007/s12551-021-00914-6

Cited by 4 publications

(5 citation statements)

References 156 publications

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“…31,32 assessed previously, the C-terminus of the CASQ2 has been described as highly conserved among species and involved in protein phosphorylation. 33 The second variant previously reported in stillbirth is a KCNE1:c.253G>A variant that was detected in 2 cases in our cohort. It represents a known KCNE1-D85N variant, which has previously been reported to be significantly more frequent in LQTS probands 34 despite also being present in 0.94% of the gnomAD population.…”

Section: Discussionmentioning

confidence: 59%

“…The variant c.2092G>A in LDB3 has been reported in four different cardiomyopathy patients in previous studies: in a 2-year-old with aborted sudden cardiac death and a severe form of hypertrophic cardiomyopathy, 45 a child with dilated cardiomyopathy, 46 and two other cases with dilated cardiomyopathy. 33,47 Our stillbirth cases all had normal autopsy results; however, this does not exclude the possibility of dilated/hypertrophic cardiomyopathy becoming detectable in the first years of life. Even though these reports do not provide any final conclusions about the variants' pathogenicity, we believe that their repeated occurrence in cardiac disease patients and their relatively low prevalence in the control database point towards their possible clinical significance.…”

Section: Four Identified Variants Have Been Previously Reported In Anmentioning

confidence: 79%

“…The study cohort consisted of 13 male and 6 female fetuses. The median fetal gestational age at stillbirth was 32 (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39) weeks. The median weight of stillborn fetuses was 1800 (410-3710) g with a median length of 42 (28 -54) cm (Table 2).…”

Section: Maternal and Fetal Baseline Characteristicsmentioning

confidence: 99%

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Further exploration of cardiac channelopathy and cardiomyopathy genes in stillbirth

Merc,

Kotnik,

Peterlin

et al. 2024

Prenatal Diagnosis

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ObjectiveTo explore genetic variation including whole genome copy number variation and sequence analysis of 98 genes associated with pediatric or adult cardiomyopathies, cardiac channelopathies, and sudden death in an unexplained intrauterine fetal death cohort.MethodsThe study population included 55 stillbirth cases that remained unexplained after thorough postmortem examination, excluding maternal, fetal, and placental causes of stillbirth. Molecular karyotyping was performed in 55 cases and the trio exome sequencing approach was applied in 19 cases.ResultsThe analysis revealed six rare variants with predicted effects on protein function in six genes (CASQ2, DSC2, KCNE1, LDB3, MYH6, and SCN5A) previously reported in cases of stillbirth or severe early onset pediatric cardiac related phenotypes. When applying strict American College of Genetics and Genomics classification guidelines, these are still variants of uncertain significance.ConclusionsSeveral potentially stillbirth‐related genetic variants were detected in our cohort, adding to the growing literature on cardiac phenotype gene variation in stillbirth. However, the mechanisms of action, gene‐gene interaction, and contribution of the uterine environment are still to be deciphered. In order to advance our knowledge of the genetics of unexplained fetal death, there is an evident need for international collaboration and field standardization.

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Section: Discussionmentioning

confidence: 59%

Section: Four Identified Variants Have Been Previously Reported In Anmentioning

confidence: 79%

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Further exploration of cardiac channelopathy and cardiomyopathy genes in stillbirth

Merc,

Kotnik,

Peterlin

et al. 2024

Prenatal Diagnosis

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“…It is associated with RyR2 via the SR integral proteins triadin and junctin, as well as directly interacting with the S1S2 luminal loop of RyR2 [ 42 , 43 ]. It is generally believed that CSQ2 exerts an inhibitory effect on RyR2 Ca 2+ release (reviewed in [ 44 ]). CSQ2 knockout mouse models present with stress-induced arrhythmia indicating that CSQ2 plays an important role in the cardiac function [ 45 , 46 ].…”

Section: Physiological Ryr2 Regulatorsmentioning

confidence: 99%

“…Initially described as the recessive form of CPVT (CPVT2), autosomal dominant mutations have also been reported [ 47 , 48 , 49 ]. CPVT-linked CSQ2 mutations may result in impaired Ca 2+ buffering, multimer formation and/or RyR2 regulation [ 41 , 44 , 50 ].…”

Section: Physiological Ryr2 Regulatorsmentioning

confidence: 99%

Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease

Fowler

Zissimopoulos

2022

Biomolecules

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The ryanodine receptor (RyR2) has a critical role in controlling Ca2+ release from the sarcoplasmic reticulum (SR) throughout the cardiac cycle. RyR2 protein has multiple functional domains with specific roles, and four of these RyR2 protomers are required to form the quaternary structure that comprises the functional channel. Numerous mutations in the gene encoding RyR2 protein have been identified and many are linked to a wide spectrum of arrhythmic heart disease. Gain of function mutations (GoF) result in a hyperactive channel that causes excessive spontaneous SR Ca2+ release. This is the predominant cause of the inherited syndrome catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, rare hypoactive loss of function (LoF) mutations have been identified that produce atypical effects on cardiac Ca2+ handling that has been termed calcium release deficiency syndrome (CRDS). Aberrant Ca2+ release resulting from both GoF and LoF mutations can result in arrhythmias through the Na+/Ca2+ exchange mechanism. This mini-review discusses recent findings regarding the role of RyR2 domains and endogenous regulators that influence RyR2 gating normally and with GoF/LoF mutations. The arrhythmogenic consequences of GoF/LoF mutations will then be discussed at the macromolecular and cellular level.

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Biophysical Reviews: from the umbra of 2020–2021 into the antumbra of 2022

Hall

2022

Biophys Rev

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This sub-Editorial for Volume 14 Issue 1 (2022) first makes comment on the current issue and then describes matters of interest related to the journal’s activities in 2022—chief among which are (i.) the announcement of the winner of the 2022 Michèle Auger Award for Young Scientists’ Independent Research, (ii.) an outline of this year’s finalized Special Issue (SI) lineup, (iii.) a description of a new production service offered by Springer to those submitting to the Biophysical Reviews journal, and (iv.) an introduction of newly appointed members of the Biophysical Reviews’ Editorial Board.

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The function and regulation of calsequestrin-2: implications in calcium-mediated arrhythmias

Cited by 4 publications

References 156 publications

Further exploration of cardiac channelopathy and cardiomyopathy genes in stillbirth

Further exploration of cardiac channelopathy and cardiomyopathy genes in stillbirth

Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease

Biophysical Reviews: from the umbra of 2020–2021 into the antumbra of 2022

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