Original articleCardiac troponin I mutations in Australian families with hypertrophic cardiomyopathy: clinical, genetic and functional consequences
Introduction
Hypertrophic cardiomyopathy (HCM) is a primary disorder of the myocardium characterised by cardiac hypertrophy in the absence of other loading conditions such as hypertension [1]. The prevalence of disease is approximately 1 in 500 of the general population [2]. The clinical course of HCM is variable, with inter- and intra-familial variations ranging from benign asymptomatic disease to a malignant phenotype with a high-risk of cardiac failure or sudden cardiac death [3]. Genetic studies over the last 15 years have shown that HCM is an autosomal dominant condition caused by defects in at least 11 genes, the majority of which encode sarcomeric proteins [4].
Cardiac troponin I (cTnI) is an important component of the troponin complex, the main function of which is to regulate cardiac muscle contraction and relaxation. This regulation is mediated by conformational changes in these three molecules (cTnI, cTnT, cTnC) in response to changes in intracellular calcium. cTnI is an inhibitory molecule, which locks the actin-myosin interaction until intracellular calcium levels are elevated at which time the inhibitory effects are removed and contraction occurs. Mutations in the cTnI gene have been identified in few families with HCM, and more recently, in families with restrictive cardiomyopathy and recessively inherited idiopathic dilated cardiomyopathy [5], [6], [7]. In HCM, relatively little is known about the clinical spectrum of disease caused by mutations in cTnI and how these mutations may result in cardiac hypertrophy and clinical disease.
The aim of the present study was to determine the clinical and genetic spectrum of families with HCM caused by mutations in the cTnI gene, and to evaluate the functional consequences of these mutations in how they alter interactions with the other components of the troponin complex.
Section snippets
Patients
Patients were all recruited from within Australia and referred for analysis at the HCM Clinic at Royal Prince Alfred Hospital in Sydney. Clinical evaluation was performed as described previously [8], which included a full clinical history and physical examination, ECG and echocardiography. A sudden cardiac death event was defined as death occurring within 1 h of symptoms in an individual with HCM, or a resuscitated cardiac arrest related to HCM. Diagnostic criteria for HCM were defined in
Results
A total of 120 families were evaluated and screened for mutations in the cTnI gene. Disease-causing mutations were identified in four families (3.3%). The clinical features of these four families are summarised in Table 1. Sudden cardiac death occurred in families FC (II:1) and X (III:3); individual II:1 died suddenly at age 15 years during rest while individual III:3 died while running at age 27 years. A documented cardiac arrest followed by successful resuscitation was seen in families J
Discussion
This study describes frequency of mutations in the cTnI gene in Australian families with HCM. A disease-causing mutation was identified in 3.3% of families tested. In all families where a mutation in the cTnI gene was identified, there was at least one affected member who had died suddenly, or a living member who had a documented previous cardiac arrest. The age of presentation was variable, ranging from 15 to 68 years. These mutations resulted in a functional disruption of the normal
Acknowledgements
C.S. is the recipient of a National Health and Medical Research Council Practitioner Fellowship. A.D. is the recipient of an Australian Postgraduate Award. The research is supported by project grants from the National Heart Foundation and the National Health and Medical Research Council of Australia.
References (24)
- et al.
The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms
Cell
(2001) - et al.
Hypertrophic cardiomyopathy: from “heart tumour” to a complex molecular genetic disorder
Heart Lung Circ.
(2004) - et al.
Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy
Lancet
(2004) - et al.
Long term follow-up of implantable cardioverter-defibrillator therapy for hypertrophic cardiomyopathy
Am. J. Cardiol.
(2004) - et al.
Deletion in the cardiac troponin I gene in a family from northern Sweden with hypertrophic cardiomyopathy
J. Mol. Cell. Cardiol.
(2000) - et al.
Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy
Lancet
(2001) - et al.
Functional consequences of the mutations in human cardiac troponin I gene found in familial hypertrophic cardiomyopathy
J. Mol. Cell. Cardiol.
(2001) - et al.
Altered regulatory properties of human cardiac troponin I mutants that cause hypertrophic cardiomyopathy
J. Biol. Chem.
(2000) - et al.
Functional analysis of a troponin I (R145G) mutation associated with familial hypertrophic cardiomyopathy
J. Biol. Chem.
(2002) - et al.
Progression of left ventricular hypertrophy and the angiotensin-converting enzyme (ACE) gene polymorphism in hypertrophic cardiomyopathy
Int. J. Cardiol.
(2004)
A polymorphic modifier gene alters the hypertrophic response in a murine model of familial hypertrophic cardiomyopathy
J. Mol. Cell. Cardiol.
Hypertrophic cardiomyopathy: from gene defect to clinical disease
Cell Res.
Cited by (42)
Current RNA strategies in treating cardiovascular diseases
2024, Molecular TherapyTNNI3 and KCNQ1 co-inherited variants in a family with hypertrophic cardiomyopathy and long QT phenotypes: A case report
2021, Molecular Genetics and Metabolism ReportsCitation Excerpt :The prediction tools used to evaluate the impact of the variant on the protein gave conflicting opinions: SIFT: deleterious, PolyPhen: benign, Align GVGD: C0. Other missense variants have been reported at the same codon, independently classified as pathogenic or likely pathogenic, in patients with HCM [15]. In Atlas of Cardiac Genetic Variations (https://www.cardiodb.org/acgv/) the c.592C>G is classified as VUS favor pathogenic.
The evolutionarily conserved C-terminal peptide of troponin I is an independently configured regulatory structure to function as a myofilament Ca<sup>2+</sup>-desensitizer
2019, Journal of Molecular and Cellular CardiologyThe functional significance of the last 5 residues of the C-terminus of cardiac troponin i
2016, Archives of Biochemistry and BiophysicsCitation Excerpt :Because of the high sensitivity of the Checkmate mammalian two-hybrid system, differences in relative affinity between test proteins could be readily detected. This system has already been shown to be able to detect changes in functional interactions between Tn subunits [40]. Interaction between cTnT (pACT) and different cTnIs (pBIND) measured using the two-hybrid system showed that the binding between cTnT-cTnI was decreased when cTnI was lacking either 3 or 5 C-terminal residues (cTnI Δ3 or Δ5) (Fig. 2A).