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Table 4 Pathogenic gene mutations associated with ARVC

From: Sudden cardiac death: focus on the genetics of channelopathies and cardiomyopathies

Mutated gene Encoded protein Functional alteration Genotype
TGF-β3 Transforming growth factor β Overexpression of TGF-β protein, leading to myocardial fibrosis [136, 137] ARVC1
RYR2 Ryanodine receptor Mutations appear to unblock the channel, resulting in hyperactivation/hypersensitization [138, 139] ARVC2
Unknown, chromosome 14q23–q24 (locus D14S42) Unknown Unknown [140] ARVC3
TTN Titin Increased vulnerability to proteolysis and degradation [141] ARVC4
TMEM43 Transmembrane protein 43, a nuclear membrane organizer It has been hypothesized that TMEM43 is a member of an adipogenic pathway regulated by PPARγ. Therefore, its dysregulation may impact the entire pathway, thus explaining the fibrofatty replacement of the myocardium in ARVC patients [97] ARVC5
Unknown, chromosome 10p12-p14 Unknown Unknown [142] ARVC6
DES Desmin, the intermediate filament protein expressed by cardiac cells Aggresome formation [143] ARVC7
DSP Desmoplakin Altered binding to plakoglobin and plakophilin [92] ARVC8
PKP2 Plakophilin-2 Disruption of functionally important domains of the PKP2 protein [94, 144] ARVC9
DSG2 Desmoglein-2 Possible change in affinity and abolition of adhesive capacity [91] ARVC10
DSC2 Desmocollin-2 Frameshifts and premature termination codons, leading to a completely nonfunctional mutant protein with no adhesive capacity [93] ARVC11
JUP Junctional plakoglobin Increased expression of adipogenic factors [90] ARVC12
PLN Phospholamban It has been hypothesized that mutant phospholamban may impair SERCA2a activity, leading to calcium homeostasis impairment, which in turn may result in desmosomal disassembly [145] Others
LMNA Lamin A/C Increase in nuclear deformation, fragmentation of chromatin, and abnormal mechanotransduction, leading to impaired ability of the cell and nuclei to resist mechanical stress [146] Others
SCN5A α-subunit of the cardiac sodium channel Nav1.5 Loss of function [147] Others
CTNNA3 α-T-catenin, which binds to plakophilins, participating in adhesion between cardiomyocytes Impaired interaction with β-catenin and increased dimerization potential [148] Others