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 |