title: A novel de novo mutation in the desmin gene causes desmin myopathy with toxic aggregates.
abstract: OBJECTIVE
  To determine the cause and pathogenic mechanisms of a 21-year-old patient's cardioskeletal myopathy. The patient's muscle atrophy and weakness began in distal parts of limbs; cardiac and facial muscles were later involved.
  
  
  BACKGROUND
  Desmin myopathy is a skeletal myopathy often associated with cardiomyopathy, caused by mutations in the desmin gene and characterized by desmin accumulation in affected muscle fibers, a leading marker of myofibrillar myopathies. Two kinds of deletions and seven missense mutations in the desmin gene have been identified.
  
  
  METHODS
  Clinical examination, electron microscopy of muscle tissue, two-dimensional gel electrophoresis, DNA sequencing, restriction enzyme analysis, and gene transfection were performed.
  
  
  RESULTS
  Electron microscopy showed disruption of sarcomeres at Z discs and electron-dense aggregates in biopsied skeletal and heart muscle. Two-dimensional gel electrophoresis of the patient's skeletal muscle proteins showed massive accumulation of desmin. The authors identified a novel desmin mutation, L385P in one allele in the carboxyl end of the rod domain 2B in the patient's leukocytes and skeletal muscle; neither parent had the mutation. Serologic study and DNA markers confirmed the de novo mutation. A peptide harboring desmin rod domains 2A and 2B with L385P tagged with green fluorescent protein induced cytoplasmic aggregates, nuclear DNA condensation, and cell death.
  
  
  CONCLUSIONS
  A novel de novo mutation, L385P, causes desmin myopathy. An expression study indicated the toxic effect of the L385P mutation.
authors.affiliation: First Department of Internal Medicine, Akita University School of Medicine, Hondo, Japan. masashir@med.akita-u.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Sugawara
authors.forename: K
authors.initials: K
authors.lastname: Kato
authors.forename: M
authors.initials: M
authors.lastname: Komatsu
authors.forename: C
authors.initials: C
authors.lastname: Wada
authors.forename: K
authors.initials: K
authors.lastname: Kawamura
authors.forename: P S
authors.initials: PS
authors.lastname: Shindo
authors.forename: P N
authors.initials: PN
authors.lastname: Yoshioka
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
authors.forename: S
authors.initials: S
authors.lastname: Watanabe
authors.forename: I
authors.initials: I
authors.lastname: Toyoshima
mesh_terms: D000328:Adult; D003893:Desmin / Q000032:analysis / Q000235:genetics*; D006801:Humans; D008297:Male; D009132:Muscles / Q000000981:diagnostic imaging / Q000378:metabolism; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D014057:Tomography, X-Ray Computed
chemical_list: D003893:Desmin