title: Noncompaction of the ventricular myocardium is associated with a de novo mutation in the beta-myosin heavy chain gene.
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 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.
authors.affiliation: Cologne Center for Genomics and Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Birgit S
authors.initials: BS
authors.lastname: Budde
authors.forename: Priska
authors.initials: P
authors.lastname: Binner
authors.forename: Stephan
authors.initials: S
authors.lastname: Waldmüller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Höhne
authors.forename: Wulf
authors.initials: W
authors.lastname: Blankenfeldt
authors.forename: Sabine
authors.initials: S
authors.lastname: Hassfeld
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brömsen
authors.forename: Anastassia
authors.initials: A
authors.lastname: Dermintzoglou
authors.forename: Marcus
authors.initials: M
authors.lastname: Wieczorek
authors.forename: Erik
authors.initials: E
authors.lastname: May
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kirst
authors.forename: Carmen
authors.initials: C
authors.lastname: Selignow
authors.forename: Kirsten
authors.initials: K
authors.lastname: Rackebrandt
authors.forename: Melanie
authors.initials: M
authors.lastname: Müller
authors.forename: Roger S
authors.initials: RS
authors.lastname: Goody
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Vosberg
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Scheffold
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D002883:Chromosomes, Human, Pair 14; D005260:Female; D008040:Genetic Linkage; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: D018995:Myosin Heavy Chains