Whole exome sequencing identifies the TNNI3K gene as a cause of familial conduction system disease and congenital junctional ectopic tachycardia

Xi, Yanwei; Honeywell, Christina; Zhang, Dapeng; Schwartzentruber, Jeremy; Beaulieu, Chandree L.; Tétreault, Martine; Hartley, Taila; Marton, Jennifer; Vidal, Silvia M.; Majewski, Jacek; Aravind, L.; Gollob, Michael H.; Boycott, Kym M.; Gow, Robert M.

doi:10.1016/j.ijcard.2015.03.130

Cited by 32 publications

(41 citation statements)

References 10 publications

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“…Similarly, we do not yet know the upper limit of MNDCMs that the mammalian heart can accommodate. Two human families with conduction system disease (tachyarrhythmia) have been identified to carry nonsynonymous coding region point mutations in the TNNI3K gene 44,45 . If TNNI3K is associated with cardiomyocyte cell cycle progression, one possibility is that interference with the process of becoming polyploid, such as perhaps occurs in these two families, might lead to functional defects such as tachyarrhythmia.…”

Section: Discussionmentioning

confidence: 99%

Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration

Patterson¹,

Barske²,

Handel³

et al. 2017

Nat Genet

276

301

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Adult mammalian cardiomyocyte regeneration after injury is thought to be minimal. Mononuclear diploid cardiomyocytes (MNDCMs), a relatively small subpopulation in the adult heart, may account for the observed degree of regeneration, but this has not been tested. We surveyed 120 inbred mouse strains and found that the frequency of adult mononuclear cardiomyocytes was surprisingly variable (>7-fold). Cardiomyocyte proliferation and heart functional recovery after coronary artery ligation both correlated with pre-injury MNDCM content. Using genome-wide association, we identified Tnni3k as one gene that influences variation in this composition and demonstrated that Tnni3k knockout resulted in elevated MNDCM content and increased cardiomyocyte proliferation after injury. Reciprocally, overexpression of Tnni3k in zebrafish promoted cardiomyocyte polyploidization and compromised heart regeneration. Our results corroborate the relevance of MNDCMs in heart regeneration. Moreover, they imply that intrinsic heart regeneration is not limited nor uniform in all individuals, but rather is a variable trait influenced by multiple genes.

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Section: Discussionmentioning

confidence: 99%

Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration

Patterson¹,

Barske²,

Handel³

et al. 2017

Nat Genet

276

301

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“…8 Multiple gene deletions like the angiotensin-converting enzyme insertion/deletion (ACE I/D) and troponin I-interacting kinase (TNNI3K) have been implicated to predispose to CJET and POJET. [9][10][11] TNNI3K is a cardiac-specific gene, encoding a cardiac troponin I-interacting kinase. Mutations here or in its gatekeeper could lead to altered phosphorylation of its substrates, such as cardiac troponin I, and may result in cardiac dysfunction, cardiac arrhythmia, and dilated cardiomyopathy.…”

Section: Etiopathophysiology and Mechanismmentioning

confidence: 99%

Junctional ectopic tachycardia in infants and children

Kylat

Samson

2019

Journal of Arrhythmia

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Tachyarrhythmias originating in the atrioventricular (AV) node and AV junction including the bundle of His complex (BH) are called junctional tachycardia (JT) or junctional ectopic tachycardia (JET). Congenital JET (CJET) is a rare arrhythmia that occurs in patients without a preceding cardiac surgery and can be refractory to medical therapy and associated with high morbidity and mortality. CJET has a high rate of morbidity and mortality with death occurring in 35% of cases. JET occurring within 72 hours after cardiac surgery is referred to as postoperative JET (POJET) and caused by direct trauma, ischemic, or stretch injury to the AV conduction tissues during surgical repair of congenital heart defects. Focal junctional tachycardia (FJT) is also known as automatic junctional tachycardia and includes paroxysmal or non‐paroxysmal forms. We discuss a staged approach to therapy with improved pharmacological therapies and the use of catheter‐based therapies.

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“…This mutation results in the early appearance of stop codon which is anticipated to produce truncated protein lacking partial protein kinase domain along with the C-terminus. For all we know, a premature termination TA B L E 3 Comparison of clinical presentation of cases with TNNI3K mutation Theis, et al (2014) 16 Xi, et al (2015) 17 Fan, et al (2018) 18 Podliesna, et al (2019) 19 Podliesna, et al (2019) 19 Podliesna, codon (PTC) may result in loss of function (LOF) through NMD. 23,24 NMD refers to rapid degradation of mRNAs in transcripts harboring a PTC existing in all eukaryotic cells, which prevents the synthesis of truncated and potentially toxic proteins.…”

Section: Discussionmentioning

confidence: 99%

“…To date, there are only four mutations in TNNI3K that have been found to be relevant with cardiovascular diseases, including three missense mutations and one splicing mutation. [16][17][18][19] Here, we found that a nonsense variant in TNNI3K (NM_015978.2:c.1441C > T), which was not seen in the human gene mutation database (HGMD), may be the cause of cardiac abnormalities.…”

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confidence: 90%

Identification of a nonsense mutation in TNNI3K associated with cardiac conduction disease

Liu

et al. 2020

Clinical Laboratory Analysis

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Background Cardiac conduction disease (CCD) is a common cardiovascular disease which can lead to life‐threatening conditions. The importance of heredity in CCD has been realized in recent years. Several causal genes have been found to be implicated in CCD such as SCN5A, TRPM4, SCN1B, TNNI3K, LMNA, and NKX2.5. To date, only four genetic mutations in TNNI3K have been identified related to CCD. Methods Whole‐exome sequencing (WES) was carried out in order to identify the underlying disease‐causing mutation in a Chinese family with CCD. The potential mutations were confirmed by Sanger sequencing. Real‐time qPCR was used to detect the level of TNNI3K mRNA expression. Results A nonsense mutation in TNNI3K (NM_015978.2: g.170891C > T, c.1441C > T) was identified in this family and validated by Sanger sequencing. Real‐time qPCR confirmed that the level of TNNI3K mRNA expression was decreased compared with the controls. Conclusions This study found the first nonsense TNNI3K mutation associated with CCD in a Chinese family. TNNI3K harboring the mutation (c.1441C > T) implicated a loss‐of‐function pathogenic mechanism with an autosomal dominant inheritance pattern. This research enriches the phenotypic spectrum of TNNI3K mutations, casting a new light upon the genotype‐phenotype correlations between TNNI3K mutations and CCD and indicating the importance of TNNI3K screening in CCD patients.

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Whole exome sequencing identifies the TNNI3K gene as a cause of familial conduction system disease and congenital junctional ectopic tachycardia

Cited by 32 publications

References 10 publications

Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration

Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration

Junctional ectopic tachycardia in infants and children

Identification of a nonsense mutation in TNNI3K associated with cardiac conduction disease

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