Original article
Cardiac troponin I mutations in Australian families with hypertrophic cardiomyopathy: clinical, genetic and functional consequences

https://doi.org/10.1016/j.yjmcc.2004.12.006Get rights and content

Abstract

Background. – Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder caused by mutations in sarcomeric proteins. Cardiac troponin I (cTnI) is a key switch molecule in the sarcomere. Mutations in cTnI have been identified in <1% of genotyped HCM families.

Methods. – To study the prevalence, clinical significance and functional consequences of cTnI mutations, genetic testing was performed in 120 consecutive Australian families with HCM referred to a tertiary referral centre, and results correlated with clinical phenotype. Each cTnI mutation identified was tested in a mammalian two-hybrid system to evaluate the functional effects of these mutations on troponin complex interactions.

Results. – Disease-causing missense mutations were identified in four families (3.3%). Two mutations were located at the same codon in exon 7 (R162G, R162P), and two in exon 8 (L198P, R204H). All four mutations change amino acid residues which are highly conserved and were not found in normal populations. Follow-up family screening has identified a total of seven clinically affected members in these four families, with a further four members who carry the gene mutation but have no clinical evidence of disease. Age at clinical presentation was variable (range 15–68 years) and the mean septal wall thickness was 19.3 ± 4.6 mm (range 7–33 mm) in clinically affected individuals, including children. In all four families, at least one member had a sudden cardiac death event, including previous cardiac arrest, indicating a more malignant form of HCM. All four mutations disrupted functional interactions with troponin C and T and this may account for the increased severity of disease in these families.

Conclusions. – Gene mutations in cTnI occur in Australian families with HCM with a prevalence higher than previously reported and may be associated with a clinically more malignant course, reflecting significant disruptions to troponin complex interactions.

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.

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