Genetic Animal Models for Arrhythmogenic Cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia. Although it is a rare cardiac disease, it is responsible for a significant proportion of sudden cardiac deaths, especially in athletes. The majority of patients with arrhythmogenic cardiomyopathy carry one or more genetic variants in desmosomal genes. In the 1990s, several knockout mouse models of genes encoding for desmosomal proteins involved in cell-cell adhesion revealed for the first time embryonic lethality due to cardiac defects. Influenced by these initial discoveries in mice, arrhythmogenic cardiomyopathy received an increasing interest in human cardiovascular genetics, leading to the discovery of mutations initially in desmosomal genes and later on in more than 25 different genes. Of note, even in the clinic, routine genetic diagnostics are important for risk prediction of patients and their relatives with arrhythmogenic cardiomyopathy. Based on improvements in genetic animal engineering, different transgenic, knock-in, or cardiac-specific knockout animal models for desmosomal and nondesmosomal proteins have been generated, leading to important discoveries in this field. Here, we present an overview about the existing animal models of arrhythmogenic cardiomyopathy with a focus on the underlying pathomechanism and its importance for understanding of this disease. Prospectively, novel mechanistic insights gained from the whole animal, organ, tissue, cellular, and molecular levels will lead to the development of efficient personalized therapies for treatment of arrhythmogenic cardiomyopathy.

Keywords: animal models of human disease; arrhythmogenic cardiomyopathy; desmosomes; genetics; mouse; sudden death; zebrafish.

FIGURE 1

Genes associated with arrhythmogenic cardiomyopathy according to the year of discovery. Colors indicate the subcellular location and/or functional association. Eclipses indicate genes listed by the Online Mendelian Inheritance in the Man (OMIM) database. Squares indicate further genes associated with arrhythmogenic cardiomyopathy. JUP = plakoglobin, DSP = desmoplakin, RYR2 = ryanodine receptor-2, PKP2 = plakophilin-2, TGFβ3 = transforming growth factor β3, DSC2 = desmocollin-2, DSG2 = desmoglein-2, TMEM43 = transmembrane protein member-43, SCN5A = sodium voltage-gated channel subunit 5α, DES = desmin, TTN = titin, PLN = phospholamban, LMNA = lamin A/C, CTNNA3 = αT-catenin, PPP1R13L = protein phosphatase 1 regulatory subunit 13 like, LDB3 = LIM domain binding 3, CDH2 = N-cadherin, RBM20 = RNA binding motif protein 20, TJP1 = tight junction protein-1, TP63 = tumor protein-63, LEMD2 = LEM-domain containing protein-2, SORBS2 = sorbin and SH3 domain containing protein-2, ILK = integrin linked kinase, FLNC = filamin-C, ACTN2 = actinin α2, SORBS2 = sorbin, and SH3 = domain containing protein-2.

FIGURE 2

Schematic overview of cardiac desmosomes. DSC2 = desmocollin-2, DSG2 = desmoglein-2, PKP2 = plakophilin-2, PG = plakoglobin, DSP = desmoplakin.

FIGURE 3

Schematic overview of animal models for desmosomal genes according to the year of publication. AAV = adeno associated virus; bp = base pair, cKO = cardiac specific knockout; ciKO = cardiac specific, inducible knockout; cidKO = cardiac specific, inducible double knockout; gKO = global knockout; het = heterozygous; hom = homozygous; KD = knockdown; KI = knock-in. [1] (Ruiz et al., 1996); [2] (Bierkamp et al., 1996); [3] (Gallicano et al., 1998); [4] (Eshkind et al., 2002); [5] (Grossmann et al., 2004); [6] (Garcia-Gras et al., 2006; Cheedipudi et al., 2019); [7] (Yang et al., 2006); [8] (Kirchhof et al., 2006; Fabritz et al., 2011); [9] (Heuser et al., 2006); [10] (Pilichou et al., 2009; Rizzo et al., 2012); [11] (Martin et al., 2009); [12] (Krusche et al., 2011; Kant et al., 2012; Buck et al., 2018); [13] (Lombardi et al., 2011); [14] (Li et al., 2011); [15] (Li et al., 2011); [16] (Cerrone et al., 2012; Leo-Macias et al., 2015); [17] (Gomes et al., 2012); [18] (Swope et al., 2012); [19] (Moriarty et al., 2012); [20] (Lyon et al., 2014); [21] (Rimpler, 2014); [22] (Asimaki et al., 2014); [23] (Cruz et al., 2015); [24] (Mezzano et al., 2016); [25] (Herbert Pratt et al., 2015); [26] (Kant et al., 2015); [27] (Zhang et al., 2015); [28] (Moncayo-Arlandi et al., 2016); [29] (Chelko et al., 2016); [30] (Cerrone et al., 2017); [31] (Brodehl et al., 2017); [32] (Calore et al., 2019); [33] (Giuliodori et al., 2018); [34] (Hamada et al., 2020).

FIGURE 4

Schematic overview of animal models for non-desmosomal genes according to the year of publication. bp = base pair, KD = knock-down; cKO = cardiac specific knock-out; ciKO = cardiac specific, inducible knock-out; gKO = global knock-out; hom = homozygous; KI = knock-in. N.A. = not assessed. [1] (Kaartinen et al., 1995); [2] (Li et al., 1996; Capetanaki et al., 1997); [3] (Takeshima et al., 1998); [4] (Chu et al., 1998); [5] (Mills et al., 1999); [6] (Sullivan et al., 1999; Nikolova et al., 2004); [7] (Ferreira-Cornwell et al., 2002); [8] (Kostetskii et al., 2005; Li et al., 2005); [9] (Dalkilic et al., 2006); [10] (White et al., 2006; Quang et al., 2015); [11] (Haghighi et al., 2006); [12] (Liu et al., 2006); [13] (Kannankeril et al., 2006); [14] (Bendig et al., 2006; Pott et al., 2018); [15] (Katsuno et al., 2008); [16] (Kostareva et al., 2008); [17] (Gramlich et al., 2009); [18] (Zheng et al., 2009); [19] (Vogel et al., 2009); [20] (Li et al., 2010); [21] (Chopra et al., 2010); [22] (Watanabe et al., 2011); [23] (Koshimizu et al., 2011); [24] (Guo et al., 2012); [25] (Li et al., 2012); [26] (Shan et al., 2012); [27] (Bround et al., 2012); [28] (Haghighi et al., 2012) [29] (Huttner et al., 2013); [30] (Clemen et al., 2015; Stockigt et al., 2020); [31] (Tapia et al., 2015); [32] (Glynn et al., 2015); [33] (Zou et al., 2015); [34] (Wan et al., 2016); [35] (Khan et al., 2016; van den Hoogenhof et al., 2018); [36] (Shih et al., 2016); [37] (Begay et al., 2018); [38] (Murayama et al., 2018); [39] (Stroud et al., 2018); [40] (Huttner et al., 2018); [41] (Padron-Barthe et al., 2019); [42] (Zheng et al., 2019); [43] (Brodehl et al., 2019d); [44] (Santos-Pereira et al., 2019); [45] (Ding et al., 2019); [46] (Zhou et al., 2020).