{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T14:17:57Z","timestamp":1789222677978,"version":"build-2803163510"},"reference-count":57,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,21]],"date-time":"2021-08-21T00:00:00Z","timestamp":1629504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["AH 357\/2-1"],"award-info":[{"award-number":["AH 357\/2-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Cardiac conduction disease (CCD), which causes altered electrical impulse propagation in the heart, is a life-threatening condition with high morbidity and mortality. It exhibits genetic and clinical heterogeneity with diverse pathomechanisms, but in most cases, it disrupts the synchronous activity of impulse-generating nodes and impulse-conduction underlying the normal heartbeat. In this study, we investigated a consanguineous Pakistani family comprised of four patients with CCD. We applied whole exome sequencing (WES) and co-segregation analysis, which identified a novel homozygous missense mutation (c.1531T&gt;C;(p.Ser511Pro)) in the highly conserved kinase domain of the cardiac troponin I-interacting kinase (TNNI3K) encoding gene. The behaviors of mutant and native TNNI3K were compared by performing all-atom long-term molecular dynamics simulations, which revealed changes at the protein surface and in the hydrogen bond network. Furthermore, intra and intermolecular interaction analyses revealed that p.Ser511Pro causes structural variation in the ATP-binding pocket and the homodimer interface. These findings suggest p.Ser511Pro to be a pathogenic variant. Our study provides insights into how the variant perturbs the TNNI3K structure-function relationship, leading to a disease state. This is the first report of a recessive mutation in TNNI3K and the first mutation in this gene identified in the Pakistani population.<\/jats:p>","DOI":"10.3390\/genes12081282","type":"journal-article","created":{"date-parts":[[2021,8,22]],"date-time":"2021-08-22T21:47:52Z","timestamp":1629668872000},"page":"1282","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family"],"prefix":"10.3390","volume":"12","author":[{"given":"Shafaq","family":"Ramzan","sequence":"first","affiliation":[{"name":"Institute for Cardiogenetics, University of L\u00fcbeck, 23562 L\u00fcbeck, Germany"},{"name":"National Institute for Biotechnology and Genetic Engineering (NIBGE-C), Institute of Engineering and Applied Sciences (PIEAS), Islamabad 44000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Tennstedt","sequence":"additional","affiliation":[{"name":"Institute for Cardiogenetics, University of L\u00fcbeck, 23562 L\u00fcbeck, Germany"},{"name":"DZHK (German Research Centre for Cardiovascular Research) Partner Site Hamburg\/L\u00fcbeck\/Kiel, 23562 L\u00fcbeck, Germany"},{"name":"University Heart Center L\u00fcbeck, 23562 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5334-403X","authenticated-orcid":false,"given":"Muhammad","family":"Tariq","sequence":"additional","affiliation":[{"name":"National Institute for Biotechnology and Genetic Engineering (NIBGE-C), Institute of Engineering and Applied Sciences (PIEAS), Islamabad 44000, 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Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8433-4328","authenticated-orcid":false,"given":"Aamir","family":"Ali","sequence":"additional","affiliation":[{"name":"National Institute for Biotechnology and Genetic Engineering (NIBGE-C), Institute of Engineering and Applied Sciences (PIEAS), Islamabad 44000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4728-3357","authenticated-orcid":false,"given":"Matthias","family":"Munz","sequence":"additional","affiliation":[{"name":"Institute for Cardiogenetics, University of L\u00fcbeck, 23562 L\u00fcbeck, Germany"},{"name":"DZHK (German Research Centre for Cardiovascular Research) Partner Site Hamburg\/L\u00fcbeck\/Kiel, 23562 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Thiele","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asad Aslam","family":"Korejo","sequence":"additional","affiliation":[{"name":"National Institute of Cardiovascular Disease, Karachi 75510, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul Razzaq","family":"Mughal","sequence":"additional","affiliation":[{"name":"Faisalabad Institute of Cardiology, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Zahid","family":"Jamal","sequence":"additional","affiliation":[{"name":"National Institute of Cardiovascular Disease, Karachi 75510, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7228-428X","authenticated-orcid":false,"given":"Peter","family":"N\u00fcrnberg","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahid Mahmood","family":"Baig","sequence":"additional","affiliation":[{"name":"National Institute for Biotechnology and Genetic Engineering (NIBGE-C), Institute of Engineering and Applied Sciences (PIEAS), Islamabad 44000, Pakistan"},{"name":"Department of Biological and Biomedical Sciences, Aga Khan University, Karachi 74000, Pakistan"},{"name":"Pakistan Science Foundation (PSF), 1-Constitution Avenue, G-5\/2, Islamabad 44000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4486-6231","authenticated-orcid":false,"given":"Jeanette","family":"Erdmann","sequence":"additional","affiliation":[{"name":"Institute for Cardiogenetics, University of 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