title: Hypertrophic cardiomyopathy: from mutation to functional analysis of defective protein.
abstract: OBJECTIVE
  To analyze the genesis of hypertrophic cardiomyopathy on a large cohort of patients from molecular genetics point of view and perform the functional analysis of the 3D molecular model of defective myosin-7 protein in silico.
  
  
  METHODS
  The study enrolled 153 patients with diagnosed hypertrophic cardiomyopathy from different parts of the Czech Republic. DNA samples were analyzed for mutations in exons 21 and 22 of the MYH7 gene, which have been associated with high mutation clustering. The 3D model of human myosin-7 was built using the x-ray structure of nucleotide-free scallop myosin S1 as the structural template. We performed de novo structure prediction of mutant and wild type peptides spanning the 769-788 amino acids region of the myosin-7 protein.
  
  
  RESULTS
  The Arg870His and Asp778Val amino acid alterations were found in 2 unrelated patients with a severe form of hypertrophic cardiomyopathy. The Asp778Val variation was chosen for subsequent 3D molecular modeling in silico. The mutation of the Asp by Val not only changes the character of the interaction pattern with other amino acids or ions but Val, being a small hydrophobic amino acid, can also completely change the stability of the region.
  
  
  CONCLUSIONS
  Mutation location in the MYH7 gene and changes in amino acid composition may have a crucial negative impact on the outcome of the disease in patients with hypertrophic cardiomyopathy. In addition, a mutation that changes the charge of the amino acid is more likely to affect protein function than a conservative mutation.
authors.affiliation: Department of Anthropology and Human Genetics, Charles University, Prague, Czech Republic. capekpavel@gmail.com
authors.forename: Pavel
authors.initials: P
authors.lastname: Capek
authors.forename: Jiri
authors.initials: J
authors.lastname: Vondrasek
authors.forename: Jiri
authors.initials: J
authors.lastname: Skvor
authors.forename: Radim
authors.initials: R
authors.lastname: Brdicka
mesh_terms: D000328:Adult; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D003198:Computer Simulation; D018153:Czech Republic; D004247:DNA / Q000032:analysis; D030541:Databases, Genetic; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D009218:Myosins / Q000235:genetics*; D018570:Risk Assessment; D055815:Young Adult
chemical_list: D004247:DNA; D009218:Myosins