Abstract
Noncompaction of the ventricular myocardium (NVM) is the morphological hallmark of a rare familial or sporadic unclassified heart disease of heterogeneous origin. NVM results presumably from a congenital developmental error and has been traced back to single point mutations in various genes. The objective of this study was to determine the underlying genetic defect in a large German family suffering from NVM. Twenty four family members were clinically assessed using advanced imaging techniques. For molecular characterization, a genome-wide linkage analysis was undertaken and the disease locus was mapped to chromosome 14ptel-14q12. Subsequently, two genes of the disease interval, MYH6 and MYH7 (encoding the α- and β-myosin heavy chain, respectively) were sequenced, leading to the identification of a previously unknown de novo missense mutation, c.842G>C, in the gene MYH7. The mutation affects a highly conserved amino acid in the myosin subfragment-1 (R281T). In silico simulations suggest that the mutation R281T prevents the formation of a salt bridge between residues R281 and D325, thereby destabilizing the myosin head. The mutation was exclusively present in morphologically affected family members. A few members of the family displayed NVM in combination with other heart defects, such as dislocation of the tricuspid valve (Ebstein's anomaly, EA) and atrial septal defect (ASD). A high degree of clinical variability was observed, ranging from the absence of symptoms in childhood to cardiac death in the third decade of life. The data presented in this report provide first evidence that a mutation in a sarcomeric protein can cause noncompaction of the ventricular myocardium.
Highlights
In order to identify all cases of noncompaction within the family DU-11, transthoracic echocardiography (TTE) was employed (2D mode, M mode and color Doppler imaging)
Noncompaction of the ventricular myocardium (NVM) was observed in three generations
The morphological phenotype observed varied from apical thickening with mild trabecularization to a spongy myocardium affecting the apical half of the left ventricle
Summary
To briefly characterize the major members of this class, the most frequent disorder is ‘‘hypertrophic cardiomyopathy’’ (HCM [MIM 192600]) typically involving a hypertrophic, nondilated left ventricle often associated with left-ventricular outflow tract obstruction. HCM has been traced to a variety of mutations in genes encoding contractile proteins of the cardiac sarcomere. ‘‘Arrhythmogenic right-ventricular cardiomyopathy/dysplasia’’ (ARVC/D [MIM 609040], a rare disorder) has a broad clinical spectrum usually presenting with ventricular tachyarrhythmia, syncopes, even cardiac arrest. Autosomal mutations have been identified in LDB3, the LIM domain-binding protein 3 gene on chromosome 10 [MIM 605906] and in DTNA on chromosome 18 [MIM 601239] [10]. A previously unknown missense mutation was detected in the gene encoding the b-myosin heavy chain (MYH7), the predominant myosin isoform in the ventricular myocardium. Via an in silico analysis clues to structural and functional consequences of the mutation in the b-myosin heavy chain were obtained
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