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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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