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From the First Department of Internal Medicine (Drs. Sugawara, Kato, Komatsu, Wada, Watanabe, and Toyoshima), the Second Department of Pathology (Dr. Kawamura), and the Department of Forensic Medicine (Drs. Shindo and Yoshioka), Akita University School of Medicine, Akita; and the Department of Neurology (Dr. Tanaka), Brain Research Institute, Niigata University School of Medicine, Niigata, Japan.
Address correspondence and reprint requests to Dr. Masashiro Sugawara, First Department of Internal Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan; e-mail: masashir{at}med.akita-u.ac.jp
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.
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