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A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family
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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395014/ https://www.ncbi.nlm.nih.gov/pubmed/34440456 http://dx.doi.org/10.3390/genes12081282 |
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author | Ramzan, Shafaq Tennstedt, Stephanie Tariq, Muhammad Khan, Sheraz Noor Ul Ayan, Hafiza Ali, Aamir Munz, Matthias Thiele, Holger Korejo, Asad Aslam Mughal, Abdul Razzaq Jamal, Syed Zahid Nürnberg, Peter Baig, Shahid Mahmood Erdmann, Jeanette Ahmad, Ilyas |
author_facet | Ramzan, Shafaq Tennstedt, Stephanie Tariq, Muhammad Khan, Sheraz Noor Ul Ayan, Hafiza Ali, Aamir Munz, Matthias Thiele, Holger Korejo, Asad Aslam Mughal, Abdul Razzaq Jamal, Syed Zahid Nürnberg, Peter Baig, Shahid Mahmood Erdmann, Jeanette Ahmad, Ilyas |
author_sort | Ramzan, Shafaq |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8395014 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-83950142021-08-28 A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family Ramzan, Shafaq Tennstedt, Stephanie Tariq, Muhammad Khan, Sheraz Noor Ul Ayan, Hafiza Ali, Aamir Munz, Matthias Thiele, Holger Korejo, Asad Aslam Mughal, Abdul Razzaq Jamal, Syed Zahid Nürnberg, Peter Baig, Shahid Mahmood Erdmann, Jeanette Ahmad, Ilyas Genes (Basel) Article 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. MDPI 2021-08-21 /pmc/articles/PMC8395014/ /pubmed/34440456 http://dx.doi.org/10.3390/genes12081282 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Ramzan, Shafaq Tennstedt, Stephanie Tariq, Muhammad Khan, Sheraz Noor Ul Ayan, Hafiza Ali, Aamir Munz, Matthias Thiele, Holger Korejo, Asad Aslam Mughal, Abdul Razzaq Jamal, Syed Zahid Nürnberg, Peter Baig, Shahid Mahmood Erdmann, Jeanette Ahmad, Ilyas A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family |
title | A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family |
title_full | A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family |
title_fullStr | A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family |
title_full_unstemmed | A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family |
title_short | A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family |
title_sort | novel missense mutation in tnni3k causes recessively inherited cardiac conduction disease in a consanguineous pakistani family |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395014/ https://www.ncbi.nlm.nih.gov/pubmed/34440456 http://dx.doi.org/10.3390/genes12081282 |
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