Whole-Exome Sequencing Identifies a Novel Variant (c.1538T &gt; C) of TNNI3K in Arrhythmogenic Right Ventricular Cardiomyopathy

Xie, Ting; Yang, Yifeng; Gong, KeWei; Luo, Yong; Guo, Hui; Liu, Ruilin; Wang, Lei; Tan, Zhiping; Luo, Jinwen; Xie, Li

doi:10.3389/fcvm.2022.843837

Cited by 3 publications

(6 citation statements)

References 30 publications

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“…An article suggested that RyR2 should be removed from the causative genes for ACM as more clinical data suggest that it belongs to the CPVT-related field [ 7 ]. However, in addition to this article, there have been some recent articles suggesting that variants in RyR2 -associated genes, such as TNNI3K , may be associated with ACM [ 50 ]. In addition, the gene variants expressed in our manuscript that affect Ca 2+ release following alterations in Ca 2+ channels are also relevant to RyR2.…”

Section: Abnormalities Of Ion Channel Proteins On the Endoplasmic/sar...mentioning

confidence: 99%

Advances in Ion Channel, Non-Desmosomal Variants and Autophagic Mechanisms Implicated in Arrhythmogenic Cardiomyopathy

Jiang

Zeng

et al. 2023

CIMB

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Arrhythmogenic cardiomyopathy (ACM) is a heterogeneous disorder characterized by the replacement of cardiac myocytes with fibro-fatty tissues, leading to abnormal excitation-contraction (EC) coupling and a range of malignant events, such as ventricular tachycardia (VT), sudden cardiac death/arrest (SCD/A) and heart failure (HF). The concept of ACM has recently been ex-tended to include right ventricular cardiomyopathy (ARVC), left ventricular cardiomyopathy (ALVC) and biventricular cardiomyopathy. ARVC is generally seen as the most common type of ACM. The pathogenesis of ACM involves mutation variants in desmosomal or non-desmosomal gene loci, as well as various external factors, such as intense exercise, stress and infections. Ion channel alterations, autophagy and non-desmosomal variants are also important components in the development of ACM. As clinical practice enters the era of precision therapy, it is important to review recent studies on these topics to better diagnose and treat the molecular phase of ACM.

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Section: Abnormalities Of Ion Channel Proteins On the Endoplasmic/sar...mentioning

confidence: 99%

Advances in Ion Channel, Non-Desmosomal Variants and Autophagic Mechanisms Implicated in Arrhythmogenic Cardiomyopathy

Jiang

Zeng

et al. 2023

CIMB

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“…A significant positive correlation between TNNI3K mRNA levels and electrocardiography (ECG) PR interval duration has been reported in patients with supraventricular tachyarrhythmias [ 8 , 9 ]. Genetic variants L513P, G526D, T539A, and E768K all reduce the kinase activity of TNNI3K, identified in patients with cardiomyopathies and arrhythmias [ 10 , 11 , 12 ]. Enigmatically, a common single nucleotide polymorphism (SNP), I686T (rs3737564), that is present in up to 4% of human populations, reduced autophosphorylation and kinase activity of TNNI3K in vitro [ 13 ], implying potential effects of this kinase in cardiac diseases.…”

Section: Introductionmentioning

confidence: 99%

Expression Levels of the Tnni3k Gene in the Heart Are Highly Associated with Cardiac and Glucose Metabolism-Related Phenotypes and Functional Pathways

Orgil

Bajpai

et al. 2023

IJMS

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Background: Troponin-I interacting kinase encoded by the TNNI3K gene is expressed in nuclei and Z-discs of cardiomyocytes. Mutations in TNNI3K were identified in patients with cardiac conduction diseases, arrhythmias, and cardiomyopathy. Methods: We performed cardiac gene expression, whole genome sequencing (WGS), and cardiac function analysis in 40 strains of BXD recombinant inbred mice derived from C57BL/6J (B6) and DBA/2J (D2) strains. Expression quantitative trait loci (eQTLs) mapping and gene enrichment analysis was performed, followed by validation of candidate Tnni3k-regulatory genes. Results: WGS identified compound splicing and missense T659I Tnni3k variants in the D2 parent and some BXD strains (D allele) and these strains had significantly lower Tnni3k expression than those carrying wild-type Tnni3k (B allele). Expression levels of Tnni3k significantly correlated with multiple cardiac (heart rate, wall thickness, PR duration, and T amplitude) and metabolic (glucose levels and insulin resistance) phenotypes in BXDs. A significant cis-eQTL on chromosome 3 was identified for the regulation of Tnni3k expression. Furthermore, Tnni3k-correlated genes were primarily involved in cardiac and glucose metabolism-related functions and pathways. Genes Nodal, Gnas, Nfkb1, Bmpr2, Bmp7, Smad7, Acvr1b, Acvr2b, Chrd, Tgfb3, Irs1, and Ppp1cb were differentially expressed between the B and D alleles. Conclusions: Compound splicing and T659I Tnni3k variants reduce cardiac Tnni3k expression and Tnni3k levels are associated with cardiac and glucose metabolism-related phenotypes.

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“…Up to now, 7 TNNI3K (troponin-I interacting kinase) variants have been reported, 1–7 from which 3 with moderate-to-strong genetic evidence, for example, multigenerational cosegregation. 1,2,4 Patients harboring variants in TNNI3K present with several cardiac phenotypes including dilated cardiomyopathy (DCM), cardiac conduction disease (CCD), and supraventricular tachycardias (SVT).…”

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confidence: 99%

“…However, the evidence linking TNNI3K to human cardiac disease has thus far remained limited to family reports, some with limited genetic evidence. 1–7…”

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confidence: 99%

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Genetic Burden of TNNI3K in Diagnostic Testing of Patients With Dilated Cardiomyopathy and Supraventricular Arrhythmias

Pham

Andrzejczyk

Jurgens

et al. 2023

Circ: Genomic and Precision Medicine

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BACKGROUND: Genetic variants in TNNI3K (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between TNNI3K variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function. METHODS: We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including TNNI3K . We further performed burden testing of TNNI3K in the UK Biobank. For 2 novel TNNI3K variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays. RESULTS: We demonstrate enrichment of rare coding TNNI3K variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between TNNI3K missense (but not loss-of-function) variants and DCM and atrial fibrillation. Furthermore, we demonstrate genetic segregation for 2 rare variants, TNNI3K-p.Ile512Thr and TNNI3K-p.His592Tyr, with phenotypes consisting of DCM, cardiac conduction disease, and supraventricular tachycardia, together with increased autophosphorylation. In contrast, TNNI3K-p.Arg556_Asn590del, a likely benign variant, demonstrated depleted autophosphorylation. CONCLUSIONS: Our findings demonstrate an increased burden of rare coding TNNI3K variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic TNNI3K variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.

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Whole-Exome Sequencing Identifies a Novel Variant (c.1538T > C) of TNNI3K in Arrhythmogenic Right Ventricular Cardiomyopathy

Cited by 3 publications

References 30 publications

Advances in Ion Channel, Non-Desmosomal Variants and Autophagic Mechanisms Implicated in Arrhythmogenic Cardiomyopathy

Advances in Ion Channel, Non-Desmosomal Variants and Autophagic Mechanisms Implicated in Arrhythmogenic Cardiomyopathy

Expression Levels of the Tnni3k Gene in the Heart Are Highly Associated with Cardiac and Glucose Metabolism-Related Phenotypes and Functional Pathways

Genetic Burden of TNNI3K in Diagnostic Testing of Patients With Dilated Cardiomyopathy and Supraventricular Arrhythmias

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