Ramzan, Shafaq, Tennstedt, Stephanie ORCID: 0000-0001-9063-3087, Tariq, Muhammad ORCID: 0000-0002-5334-403X, Khan, Sheraz ORCID: 0000-0003-3207-4074, Ul Ayan, Hafiza Noor, Ali, Aamir, Munz, Matthias, Thiele, Holger, Korejo, Asad Aslam, Mughal, Abdul Razzaq, Jamal, Syed Zahid, Nuernberg, Peter, Baig, Shahid Mahmood, Erdmann, Jeanette ORCID: 0000-0002-4486-6231 and Ahmad, Ilyas (2021). A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family. Genes, 12 (8). BASEL: MDPI. ISSN 2073-4425

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Ramzan, ShafaqUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tennstedt, StephanieUNSPECIFIEDorcid.org/0000-0001-9063-3087UNSPECIFIED
Tariq, MuhammadUNSPECIFIEDorcid.org/0000-0002-5334-403XUNSPECIFIED
Khan, SherazUNSPECIFIEDorcid.org/0000-0003-3207-4074UNSPECIFIED
Ul Ayan, Hafiza NoorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ali, AamirUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Munz, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Korejo, Asad AslamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mughal, Abdul RazzaqUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jamal, Syed ZahidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baig, Shahid MahmoodUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Erdmann, JeanetteUNSPECIFIEDorcid.org/0000-0002-4486-6231UNSPECIFIED
Ahmad, IlyasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-595781
DOI: 10.3390/genes12081282
Journal or Publication Title: Genes
Volume: 12
Number: 8
Date: 2021
Publisher: MDPI
Place of Publication: BASEL
ISSN: 2073-4425
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PROTEIN-KINASE; DILATED CARDIOMYOPATHY; SYSTEM; HEART; GENE; IDENTIFICATION; MECHANISMS; DOMAIN; BLOCKMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59578

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