Exon- and contraction-dependent functions of titin in sarcomere assembly

Shih, Yu-Huan; Dvornikov, Alexey V.; Zhu, Ping; Ma, Xiao; Kim, Maengjo; Ding, Yonghe; Xu, Xiaolei

doi:10.1242/dev.139246

Cited by 31 publications

(39 citation statements)

References 45 publications

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“…This criticism also included the nomenclature of TTN nonsense variants as “TTNtv”, as this might be misleading unless truncations are proven by protein gels (Shih et al 2016). These reports raised questions on the pathogenicity of published truncating variants, especially when the conclusions are not supported by strong data such as large clinical cohorts, background frequencies in population cohorts, and mechanistic/animal studies.…”

Section: Animal Models Of Ttn Mutationsmentioning

confidence: 99%

Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy

et al. 2017

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Heart failure (HF) is a complex clinical syndrome defined by the inability of the heart to pump enough blood to meet the body’s metabolic demands. Major causes of HF are cardiomyopathies (diseases of the myocardium associated with mechanical and/or electrical dysfunction), among which the most common form is dilated cardiomyopathy (DCM). DCM is defined by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness, which leads to progressive HF. Over 60 genes are linked to the etiology of DCM. Titin (TTN) is the largest known protein in biology, spanning half the cardiac sarcomere and, as such, is a basic structural and functional unit of striated muscles. It is essential for heart development as well as mechanical and regulatory functions of the sarcomere. Next-generation sequencing (NGS) in clinical DCM cohorts implicated truncating variants in titin (TTNtv) as major disease alleles, accounting for more than 25% of familial DCM cases, but these variants have also been identified in 2–3% of the general population, where these TTNtv blur diagnostic and clinical utility. Taking into account the published TTNtv and their association to DCM, it becomes clear that TTNtv harm the heart with position-dependent occurrence, being more harmful when present in the A-band TTN, presumably with dominant negative/gain-of-function mechanisms. However, these insights are challenged by the depiction of position-independent toxicity of TTNtv acting via haploinsufficient alleles, which are sufficient to induce cardiac pathology upon stress. In the current review, we provide an overview of TTN and discuss studies investigating various TTN mutations. We also present an overview of different mechanisms postulated or experimentally validated in the pathogenicity of TTNtv. DCM-causing genes are also discussed with respect to non-truncating mutations in the etiology of DCM. One way of understanding pathogenic variants is probably to understand the context in which they may or may not affect protein–protein interactions, changes in cell signaling, and substrate specificity. In this regard, we also provide a brief overview of TTN interactions in situ. Quantitative models in the risk assessment of TTNtv are also discussed. In summary, we highlight the importance of gene–environment interactions in the etiology of DCM and further mechanistic studies used to delineate the pathways which could be targeted in the management of DCM.

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Section: Animal Models Of Ttn Mutationsmentioning

confidence: 99%

Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy

et al. 2017

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“…Deficiency in gene expression and assembly of key sarcomeric components can individually cause impairment in cardiac differentiation. Deletion of thin filament markers Tnnt2 and Tnni3 and thick filament marker Ttn in mice caused severe cardiomyopathy pinpointing the relevance that RYBP may function in the development of cardiomyopathy in humans as well [ 25 – 27 ].…”

Section: Discussionmentioning

confidence: 99%

RYBP is important for cardiac progenitor cell development and sarcomere formation

et al. 2020

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We have previously established that epigenetic regulator RING1 and YY1 binding protein (RYBP) is required for the contractility of embryonic stem (ES) cell derived cardiomyocytes (CMCs), suggesting its essential role in contractility. In order to investigate the underlying molecular events of this phenotype, we compared the transcriptomic profile of the wild type and Rybp null mutant ES cells and CMCs differentiated from these cell lines. We identified genes related to ion homeostasis, cell adhesion and sarcomeric organization affected in the Rybp null mutant CMCs, by using hierarchical gene clustering and Gene Ontology analysis. We have also demonstrated that the amount of RYBP is drastically reduced in the terminally differentiated wild type CMCs whilst it is broadly expressed in the early phase of differentiation when progenitors form. We also describe that RYBP is important for the proper expression of key cardiac transcription factors including Mesp1, Shh and Mef2c. These findings identify Rybp as a gene important for both early cardiac gene transcription and consequent sarcomere formation necessary for contractility. Since impairment of sarcomeric function and contractility plays a central role in reduced cardiac pump function leading to heart failures in human, current results might be relevant to the pathophysiology of cardiomyopathies.

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“…= 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] (…”

Section: Animal Models For Acm Associated With Mutations In Nondesmosmentioning

confidence: 99%

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

Gerull

Brodehl

2020

Front. Physiol.

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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.

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Exon- and contraction-dependent functions of titin in sarcomere assembly

Cited by 31 publications

References 45 publications

Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy

Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy

RYBP is important for cardiac progenitor cell development and sarcomere formation

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

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