Aberrant accumulation of TMEM43 accompanied by perturbed transmural gene expression in arrhythmogenic cardiomyopathy

Abstract

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Altered Expression of TMEM43 Causes Abnormal Cardiac Structure and Function in Zebrafish

“…In human patients, mutations in the nuclear envelope protein TMEM43 are responsible for severe diseases, including ACM type 5, a devastating cardiomyopathy that causes malignant arrhythmias and heart failure [ 18 , 26 , 27 ]. Despite efforts in recent in vivo studies using transgenic, knock-in, or knock-out rodent models, the pathogenic mechanisms of TMEM43-associated ACM remain still poorly understood [ 22 , 30 , 31 , 32 , 33 , 34 ]. In this study, we generated the first transgenic zebrafish model expressing two different potential pathogenic variants found in human patients under a heart-specific promoter and generated genetic mutants of tmem43 in zebrafish.…”

“…Moreover, it has been shown that already slight changes in energetics may affect the conformational stability [ 44 ]. Although, the substitution of serine to leucine might have only a minor effect on energetics, it might be sufficient to impair correct membrane topology of TMEM43, resulting in a disturbed ability to interact with other nuclear envelope or LINC complex proteins [ 22 ]. Furthermore, distorted TMEM43 appears to be destabilized, which is illustrated by the partial redistribution of TMEM43-p.S358L to the cytoplasm ( Figure 2 D,E).…”

“…However, mutations residing in non-desmosomal gene-encoding proteins with biological functions in nucleoskeletal [ 9 , 10 , 11 ] and cytoskeletal architecture [ 12 , 13 ], calcium handling [ 14 , 15 ], sodium transport [ 16 ], and cytokine signaling [ 17 ] have also been described. A heterozygous variant (c.1073C>T, p.S358L) within the transmembrane protein 43 ( TMEM43 ) gene has been unequivocally identified to cause a fully penetrant and sex-influenced form of ACM in unrelated patients around the globe [ 18 , 19 , 20 , 21 , 22 ]. Other rare TMEM43 variants (NM_024334.3(TMEM43): c.265G>A, p.V89M; c.896G>C, p.R299T; c.331C>G, p.P111L) have also been proposed to be causative for ACM [ 23 , 24 ].…”

“…TMEM43 has been shown to interact with components of the linker of nucleoskeleton and cytoskeleton (LINC) complex, such as emerin and lamins, and thus is involved in the organization of the nuclear membrane [ 28 ]. To date, several model systems, including induced pluripotent stem cell derived CMs (iPSC-CMs), transgenic mice and rats carrying the TMEM43 c.1073C>T, p.S358L variant, or Tmem43 knock-out mutations have been generated to investigate the molecular mechanism underlying ACM [ 22 , 30 , 31 , 32 , 33 , 34 , 35 ]. However, the associated phenotypes among the animal models are highly variable, suggesting a controversial role of Tmem43 in murine heart.…”

Myocardial Inflammation as a Manifestation of Genetic Cardiomyopathies: From Bedside to the Bench

“…However, this activation does not promote a typical cardiac inflammatory response, instead leading to TGFβ-mediated fibrosis [ 105 ]. On the other side, inflammatory cell infiltration was also observed in homozygous Tmem43-S358L KI rats [ 106 ]. Consistently, GSK3β inhibition in TMEM43 mutant mice resulted in a relative improvement in the contractile function [ 105 , 141 ].…”