Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations

Abstract

Restrictive cardiomyopathy (RCM) is an uncommon heart muscle disorder characterized by impaired filling of the ventricles with reduced volume in the presence of normal or near normal wall thickness and systolic function. The disease may be associated with systemic disease but is most often idiopathic. We recognized a large family in which individuals were affected by either idiopathic RCM or hypertrophic cardiomyopathy (HCM). Linkage analysis to selected sarcomeric contractile protein genes identified cardiac troponin I (TNNI3) as the likely disease gene. Subsequent mutation analysis revealed a novel missense mutation, which cosegregated with the disease in the family (lod score: 4.8). To determine if idiopathic RCM is part of the clinical expression of TNNI3 mutations, genetic investigations of the gene were performed in an additional nine unrelated RCM patients with restrictive filling patterns, bi-atrial dilatation, normal systolic function, and normal wall thickness. TNNI3 mutations were identified in six of these nine RCM patients. Two of the mutations identified in young individuals were de novo mutations. All mutations appeared in conserved and functionally important domains of the gene. This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

Figure 1

Pedigree drawings of restrictive cardiomyopathy families affected by cardiac troponin I mutations. Squares indicate male family members; circles, female family members; symbols with slash, deceased individuals; open symbols, unaffected individuals; filled symbols, individuals affected by RCM (indicated by arrows) or HCM; checkered symbols, individuals who died suddenly; question mark, unknown clinical status. Plus sign indicates presence of mutation, whereas minus sign indicates absence of mutation. Generation II of family H640 consisted of a total of 13 siblings, of which 9 were available for this investigation. Four generation-II siblings were obligate carriers of the mutation (included in the pedigree drawing with their offspring), while five remaining siblings were shown not to carry the mutation. Two of the obligate carriers (III-7, II-3) died suddenly at the age of 40. The remaining obligate carriers (II-1, II-2, II-4), reached the age of 63, 59, and 51 years, respectively. Ten sudden deaths appeared in young individuals who had a 50% chance of having inherited the disease (IV-1/2/4; III-18/20/21/22/23/26/27). Their average age of death was 25 years (16–33 years), and most had symptoms of cardiac disease prior to their death. Individual IV-13 was shown to be a healthy carrier of the mutation at the age of 5 years.

Figure 2

Clinical features of restrictive cardiomyopathy in individual H417 affected by a de novo mutation in the gene for cardiac troponin I (Arg192His). (a) Apical four-chamber echocardiogram in systole of H417 at the age of 18 with marked bi-atrial dilatation (left atrial [LA] size, 64 mm), dilatation of pulmonary veins (PV), normal-sized ventricles and normal wall thickness. LV, left ventricle; RV, right ventricle; RA, right atrium. (b) 12-lead ECG in sinus rhythm with prominent P-waves in all leads, T-wave inversions, and incomplete right bundle branch block. (c) Microscopy of heart tissue obtained postmortem with myocyte hypertrophy, abundant interstitial fibrosis, and myofibril disarray equivalent to the histological findings in HCM patients (14, 15) (hematoxylin and eosin staining, ×40).

Figure 3

Schematic representation of the human cardiac troponin I gene with the number of corresponding amino acids encoded by the gene and interaction sites with other sarcomeric contractile proteins (13, 28). The stars indicate mutations identified in patients with restrictive cardiomyopathy in numerical order: Leu144Gln identified in H38, Arg145Trp identified in H816 and H805, Ala171Thr identified in H974, Lys178Glu identified in H906, Asp190His identified in H640, and Arg192His identified in H417.