A Novel Missense Mutation in
| Autor: | Shafaq, Ramzan, 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, Ilyas, Ahmad |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Male Adolescent missense mutation Homozygote Troponin I Mutation Missense TNNI3K Middle Aged Protein Serine-Threonine Kinases Article Pedigree Consanguinity Young Adult Cardiac Conduction System Disease cardiac conduction Exome Sequencing Humans Female Genetic Predisposition to Disease Pakistan Protein Interaction Domains and Motifs Child Transcription Factors molecular modeling simulation |
| Zdroj: | Genes |
| ISSN: | 2073-4425 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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