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Article

A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family

1
Institute for Cardiogenetics, University of Lübeck, 23562 Lübeck, Germany
2
National Institute for Biotechnology and Genetic Engineering (NIBGE-C), Institute of Engineering and Applied Sciences (PIEAS), Islamabad 44000, Pakistan
3
DZHK (German Research Centre for Cardiovascular Research) Partner Site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany
4
University Heart Center Lübeck, 23562 Lübeck, Germany
5
Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany
6
National Institute of Cardiovascular Disease, Karachi 75510, Pakistan
7
Faisalabad Institute of Cardiology, Faisalabad 38000, Pakistan
8
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany
9
Department of Biological and Biomedical Sciences, Aga Khan University, Karachi 74000, Pakistan
10
Pakistan Science Foundation (PSF), 1-Constitution Avenue, G-5/2, Islamabad 44000, Pakistan
*
Author to whom correspondence should be addressed.
Academic Editors: Andreas Brodehl, Hendrik Milting and Brenda Gerull
Genes 2021, 12(8), 1282; https://doi.org/10.3390/genes12081282
Received: 7 July 2021 / Revised: 15 August 2021 / Accepted: 16 August 2021 / Published: 21 August 2021
(This article belongs to the Special Issue Recent Advance in Cardiovascular Genetics)
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>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. View Full-Text
Keywords: TNNI3K; missense mutation; molecular modeling simulation; cardiac conduction TNNI3K; missense mutation; molecular modeling simulation; cardiac conduction
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MDPI and ACS Style

Ramzan, S.; Tennstedt, S.; Tariq, M.; Khan, S.; Noor Ul Ayan, H.; Ali, A.; Munz, M.; Thiele, H.; Korejo, A.A.; Mughal, A.R.; Jamal, S.Z.; Nürnberg, P.; Baig, S.M.; Erdmann, J.; Ahmad, I. A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family. Genes 2021, 12, 1282. https://doi.org/10.3390/genes12081282

AMA Style

Ramzan S, Tennstedt S, Tariq M, Khan S, Noor Ul Ayan H, Ali A, Munz M, Thiele H, Korejo AA, Mughal AR, Jamal SZ, Nürnberg P, Baig SM, Erdmann J, Ahmad I. A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family. Genes. 2021; 12(8):1282. https://doi.org/10.3390/genes12081282

Chicago/Turabian Style

Ramzan, Shafaq, Stephanie Tennstedt, Muhammad Tariq, Sheraz Khan, Hafiza Noor Ul Ayan, Aamir Ali, Matthias Munz, Holger Thiele, Asad Aslam Korejo, Abdul Razzaq Mughal, Syed Zahid Jamal, Peter Nürnberg, Shahid Mahmood Baig, Jeanette Erdmann, and Ilyas Ahmad. 2021. "A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family" Genes 12, no. 8: 1282. https://doi.org/10.3390/genes12081282

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