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

• Published in: International journal of molecular sciences Vol. 24; no. 16; p. 12759
• Main Authors: Gu, Qingqing, Orgil, Buyan-Ochir, Bajpai, Akhilesh Kumar, Chen, Yufeng, Ashbrook, David G, Starlard-Davenport, Athena, Towbin, Jeffrey A, Lebeche, Djamel, Purevjav, Enkhsaikhan, Sheng, Hongzhuan, Lu, Lu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 14.08.2023; MDPI
• Subjects: Animals; BXD family; Carbohydrate Metabolism; Cardiac function; cardiac physiology; Cardiomyocytes; Cardiomyopathy; Cell cycle; Electrocardiography; Gene loci; Genomes; Glucose; glucose metabolism; Insulin resistance; Ischemia; Kinases; Metabolism; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Myocytes, Cardiac; Physiology; Protein Serine-Threonine Kinases; Proteins; Signal transduction; systems genetics; Tnni3k; systems genetics; BXD family; Tnni3k; glucose metabolism; cardiac physiology
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241612759

Troponin-I interacting kinase encoded by the gene is expressed in nuclei and Z-discs of cardiomyocytes. Mutations in were identified in patients with cardiac conduction diseases, arrhythmias, and cardiomyopathy. 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 -regulatory genes. WGS identified compound splicing and missense T659I variants in the D2 parent and some BXD strains (D allele) and these strains had significantly lower expression than those carrying wild-type (B allele). Expression levels of 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 -eQTL on chromosome 3 was identified for the regulation of expression. Furthermore, -correlated genes were primarily involved in cardiac and glucose metabolism-related functions and pathways. Genes , , , , , , , , , , , and were differentially expressed between the B and D alleles. Compound splicing and T659I variants reduce cardiac expression and levels are associated with cardiac and glucose metabolism-related phenotypes.