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

Shafaq Ramzan,Stephanie Tennstedt,Asad Aslam Korejo,Muhammad Tariq,Syed Zahid Jamal,Sheraz Khan,Holger Thiele,Ilyas Ahmad,Peter Nürnberg,Matthias Munz,Shahid Mahmood Baig,Aamir Ali,Abdul Razzaq Mughal,Hafiza Noor Ul Ayan,Jeanette Erdmann

doi:10.3390/genes12081282

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.

Highlights

Cardiac conduction disease (CCD) is a hypernym that encompasses numerous rare disorders in which the integrity of the heart conduction system is disrupted [1]
Both parents and healthy siblings were assessed for CCD but no relevant clinical features were detected
As amino acid orientation and interactions in the ATP-binding pocket are critical for the activity of the complex [51], these findings suggest that the mutation alters the ATPase activity of TNNI3K

Summary

Introduction

Cardiac conduction disease (CCD) is a hypernym that encompasses numerous rare disorders in which the integrity of the heart conduction system is disrupted [1]. In CCD, anatomical or functional alterations in the conduction system lead to slowing or blocking of impulse induction, which can cause syncope or sudden death. Structural CCD with abnormal impulse propagation is most often a secondary impact of congenital heart disease or histological heart abnormalities [1,2]. CCD is primarily due to dysfunction of the sinoatrial node (SAN), atrioventricular node (AVN), His-bundle, the right or left bundle branch (RBB or LBB) Purkinje system, or the peripheral ventricular conduction system (PVCS) [3,4]. The molecular and cellular mechanisms underlying CCD are diverse; regardless of its cause, pacemaker therapy is a potential cure. Understanding of genetic contributions to cardiac electrophysiology has been advanced by familial clustering and GWAS studies, the latter approach has had limited success in identification of genetic variants associated with phenotypic consequences [5,6]

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