Molecular adaptation to calsequestrin 2 (CASQ2) point mutations leading to catecholaminergic polymorphic ventricular tac
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ORIGINAL PAPER
Molecular adaptation to calsequestrin 2 (CASQ2) point mutations leading to catecholaminergic polymorphic ventricular tachycardia (CPVT): comparative analysis of R33Q and D307H mutants Giorgia Valle1 · Michael Arad2 · Pompeo Volpe1 Received: 22 April 2020 / Accepted: 29 August 2020 © The Author(s) 2020
Abstract Homozygous 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. Keywords Cathecolaminergic polymorphic ventricular tachycardia · CASQ2 mutations · Degradative pathways · Small heat shock proteins Abbreviations Bcl-2 B cell lymphoma-2 CASQ2 cardiac calsequestrin CMA Chaperone-mediated autophagy CNX Calnexin CRT Calreticulin EDEM-1 ER degradation-enhancing alpha-mannosidase-like protein 1 ER/SR Endoplasmic/sarcoplasmic reticulum ERAD Endoplasmic reticulum-associated degradation GRP78 Glucose-related protein78 GRP94 Glucose-related protein94 sHSP Small heat shock protein KI Knock-in KO knock-out SEL1L Suppressor/enhancer of Lin12-like STIM1 Stromal interaction molecule 1 TRPC Transient receptor potential channel WT Wild type * Pompeo Volpe [email protected] 1
Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy
Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
2
Introduction Homozygous mutations in the cardiac calsequestrin (CASQ2) gene are linked to the recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), a life-threatening genetic disease causing dramatic episodes of cardiac arrhythmia and syncope, in the absence of macroscopic structural abnormalities. The genetic background of CPVT is heterogeneous (Faggioni et al. 2012; Al-Hassnan et al. 2013): there are deletions, null mutations as well as missense point mutations which have been studied in some detail, i.e., an arginine residue changed to glutamine at position 33 (R33Q) and an aspartic residue changed to histidine at position 307 (D307H) (Rizzi et al. 2008; Song et al. 2007). Studies of cellular and molecular pathogenesis of CPVT have unravelled adaptive processes that adjust and cope with the presence of a mutant CASQ2 protein and/or with the substantial lack of CASQ2 (Song et al. 2007; Valle et al. 2014). The common pathogenetic feature appears to be the reduction/lack of CASQ2 since the CASQ2 null (KO) model is associated with
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