Journal Article

Noncompaction of the Ventricular Myocardium Is Associated with a De Novo Mutation in the β-Myosin Heavy Chain Gene

Nürnberg, Peter, Blankenfeldt, Wulf, Budde, Birgit S., Binner, Priska, Kirst, Elisabeth, Höhne, Wolfgang, Waldmüller, Stephan, Brömsen, Jürgen, Goody, Roger S., Scheffold, Thomas, Vosberg, Hans-Peter, Hassfeld, Sabine, Dermintzoglou, Anastassia, Rackebrandt, Kirsten, Müller, Melanie, Selignow, Carmen, May, Erik, Wieczorek, Marcus

2007

Overview

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 alpha- and beta-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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adolescent / Adult / Amino Acid Sequence / Amino acids / Cardiomyopathy / Cardiovascular diseases / Cardiovascular Disorders/Congenital Heart Disease / Cardiovascular Disorders/Myopathies / Chains / Child / Children / Chromosome 14 / Chromosomes / Chromosomes, Human, Pair 14 / Coronary artery disease / Dislocation / Dislocations / Female / Genes / Genetic Linkage / Genetics / Genetics and Genomics/Genetics of Disease / Genetics and Genomics/Medical Genetics / Genomes / Genomics / Heart / Heart diseases / Heart failure / Heart Ventricles - metabolism / Heart Ventricles - pathology / Humans / Imaging techniques / Linkage analysis / Male / Missense mutation / Molecular Sequence Data / Mutation / Mutation, Missense / Myocardium / Myosin / Myosin Heavy Chains - chemistry / Myosin Heavy Chains - genetics / Pediatrics / Physiology/Muscle and Connective Tissue / Proteins / Salts / Sequence Homology, Amino Acid / Tricuspid valve / Ventricle