title: A novel missense mutation, Leu390Val, in the cardiac beta-myosin heavy chain associated with pronounced septal hypertrophy in two families with hypertrophic cardiomyopathy.
abstract: OBJECTIVE
  An examination of the genetic background and phenotypic presentation of familial hypertrophic cardiomyopathy (FHC) with respect to specific mutations in the MYH7-gene encoding the cardiac beta-myosin heavy chain.
  
  
  METHODS
  Two families (n = 22) from a cohort of 67 families with FHC were studied at the National University Hospital, Rigshospitalet, Copenhagen.
  
  
  METHODS
  Clinical, non-invasive examinations of all included family members followed by molecular genetic analysis including PCR-single strand conformation polymorphism/heteroduplex (SSCP/HD) analysis and sequencing of exon 3-23 of the MYH7-gene.
  
  
  RESULTS
  We found FHC associated with a missense mutation in two families, i.e. a C > G transversion at position g10124 and a G > T transversion at position g10126 causing the change of a leucine residue at codon 390 to a valine residue. The mutation is located in the actin-binding region of the beta-myosin heavy chain. The leucine residue is evolutionarily conserved in vertebrate myosins. In the two families, the phenotypic presentations in the clinically affected were characterized by asymmetric septal hypertrophy (septum diameter 18.8 (5.0) mm (mean (SD)) with only minor involvement of the left ventricular free wall (posterior wall diameter 11.0 (2.2) mm). Furthermore, the left ventricular systolic and diastolic functions were well preserved, even at a high age. The symptomatic status of the clinically affected patients depended on the presence or absence of a concomitant left ventricular outflow tract gradient.
  
  
  CONCLUSIONS
  We report a novel missense mutation associated with FHC caused by a double nucleotide transversion. The penetrance of the mutation was not complete, but in clinically affected patients the mutation gives rise to an echocardiographic phenotype, predominantly characterized by pronounced septal hypertrophy.
authors.affiliation: Department of Medicine B, The Heart Center, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: O
authors.initials: O
authors.lastname: Havndrup
authors.forename: H
authors.initials: H
authors.lastname: Bundgaard
authors.forename: P S
authors.initials: PS
authors.lastname: Andersen
authors.forename: L A
authors.initials: LA
authors.lastname: Larsen
authors.forename: J
authors.initials: J
authors.lastname: Vuust
authors.forename: K
authors.initials: K
authors.lastname: Kjeldsen
authors.forename: M
authors.initials: M
authors.lastname: Christiansen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D006332:Cardiomegaly / Q000235:genetics*; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D004562:Electrocardiography; D005091:Exons; D006801:Humans; D007930:Leucine / Q000235:genetics; D008875:Middle Aged; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D012518:Sarcomeres / Q000235:genetics*; D014633:Valine / Q000235:genetics
chemical_list: D018995:Myosin Heavy Chains; D007930:Leucine; D014633:Valine