{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T15:50:06Z","timestamp":1765295406735,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,14]],"date-time":"2023-08-14T00:00:00Z","timestamp":1691971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["HL128350","HL151438"],"award-info":[{"award-number":["HL128350","HL151438"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms241612759","type":"journal-article","created":{"date-parts":[[2023,8,14]],"date-time":"2023-08-14T10:13:57Z","timestamp":1692008037000},"page":"12759","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Expression Levels of the Tnni3k Gene in the Heart Are Highly Associated with Cardiac and Glucose Metabolism-Related Phenotypes and Functional Pathways"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3409-8969","authenticated-orcid":false,"given":"Qingqing","family":"Gu","sequence":"first","affiliation":[{"name":"Department of Cardiology, Affiliated Hospital of Nantong University, Nantong 226001, China"},{"name":"Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Buyan-Ochir","family":"Orgil","sequence":"additional","affiliation":[{"name":"The Heart Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA"},{"name":"Children\u2019s Foundation Research Institute, Le Bonheur Children\u2019s Hospital, Memphis, TN 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akhilesh Kumar","family":"Bajpai","sequence":"additional","affiliation":[{"name":"Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yufeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Affiliated Hospital of Nantong University, Nantong 226001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7397-8910","authenticated-orcid":false,"given":"David G.","family":"Ashbrook","sequence":"additional","affiliation":[{"name":"Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8938-237X","authenticated-orcid":false,"given":"Athena","family":"Starlard-Davenport","sequence":"additional","affiliation":[{"name":"Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4182-2786","authenticated-orcid":false,"given":"Jeffrey A.","family":"Towbin","sequence":"additional","affiliation":[{"name":"The Heart Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA"},{"name":"Children\u2019s Foundation Research Institute, Le Bonheur Children\u2019s Hospital, Memphis, TN 38105, USA"},{"name":"Pediatric Cardiology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7911-2923","authenticated-orcid":false,"given":"Djamel","family":"Lebeche","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6188-7176","authenticated-orcid":false,"given":"Enkhsaikhan","family":"Purevjav","sequence":"additional","affiliation":[{"name":"The Heart Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA"},{"name":"Children\u2019s Foundation Research Institute, Le Bonheur Children\u2019s Hospital, Memphis, TN 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongzhuan","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Affiliated Hospital of Nantong University, Nantong 226001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/s00109-003-0427-x","article-title":"Cloning and characterization of a novel cardiac-specific kinase that interacts specifically with cardiac troponin I","volume":"81","author":"Zhao","year":"2003","journal-title":"J. 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