title: Structural and functional analysis of a new desmin variant causing desmin-related myopathy.
abstract: Desmin-related myopathy is a familial or sporadic disease characterized by skeletal muscle weakness and cardiomyopathy as well as the presence of intracytoplasmic aggregates of desmin-reactive material in the muscle cells. Previously, two kinds of deletions and eight missense mutations have been identified in the desmin gene and proven to be responsible for the disorder. The present study was conducted to determine structural and functional defects in a pathogenic desmin variant that caused a disabling disorder in an isolated case presenting with distal and proximal limb muscle weakness and cardiomyopathy. We identified a novel heterozygous Q389P desmin mutation located at the C-terminal part of the rod domain as the causative mutation in this case. Transfection of desmin cDNA containing the patient's mutation into C2.7, MCF7, and SW13 cells demonstrated that the Q389P mutant is incapable of constructing a functional intermediate filament network and has a dominant negative effect on filament formation. We conclude that Q389P mutation is the molecular event leading to the development of desmin-related myopathy.
authors.affiliation: Laboratoire Cytosquelette et Développement, UMR CNRS 7000, Faculté de Médecine, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Goudeau
authors.forename: A
authors.initials: A
authors.lastname: Dagvadorj
authors.forename: F
authors.initials: F
authors.lastname: Rodrigues-Lima
authors.forename: P
authors.initials: P
authors.lastname: Nédellec
authors.forename: M
authors.initials: M
authors.lastname: Casteras-Simon
authors.forename: E
authors.initials: E
authors.lastname: Perret
authors.forename: S
authors.initials: S
authors.lastname: Langlois
authors.forename: L
authors.initials: L
authors.lastname: Goldfarb
authors.forename: P
authors.initials: P
authors.lastname: Vicart
mesh_terms: D000328:Adult; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D009202:Cardiomyopathies / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D002460:Cell Line; D003459:Crystallins / Q000235:genetics; D004252:DNA Mutational Analysis; D003893:Desmin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005799:Genes, Dominant / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D007382:Intermediate Filaments / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D018908:Muscle Weakness / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D020125:Mutation, Missense / Q000235:genetics*; D020914:Myopathies, Structural, Congenital / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D003459:Crystallins; D003893:Desmin