A novel de novo mutation in the desmin gene causes desmin myopathy with toxic aggregates.
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.
Sugawara
M
M
First Department of Internal Medicine, Akita University School of Medicine, Hondo, Japan. masashir@med.akita-u.ac.jp
Kato
K
K
Komatsu
M
M
Wada
C
C
Kawamura
K
K
Shindo
P S
PS
Yoshioka
P N
PN
Tanaka
K
K
Watanabe
S
S
Toyoshima
I
I
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
D003893:Desmin