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Mutations in desmin gene have been identified in patients with cardiac and skeletal myopathy characterized by intracytoplasmic accumulation of desmin-reactive deposits and electron-dense granular aggregates. We characterized two new desminopathy families with unusual features of adult-onset, slowly progressive, diffuse skeletal myopathy and respiratory insufficiency. Progressive reduction of respiratory muscle strength became clinically detectable between the 3rd and the 8th years of illness and led to recurrent chest infections and death in one of the patients. Novel mutations, A357P and L370P, predicted to introduce proline residue into a highly conserved alpha-helical region of desmin, were identified. Proline is known to disrupt the alpha-helix. In addition, the A357P mutation distorts a unique stutter sequence that is considered to be critically important for proper filament assembly. Functional assessment in two cell-lines, one of which does and the other of which does not constitutively produce type III intermediate filaments, demonstrated the inability of mutant desmin carrying either the A357P or the L370P mutation to polymerize and form an intracellular filamentous network. The results of this study indicate that respiratory insufficiency is an intrinsic feature of disease associated with specific desmin mutations; in some patients, respiratory weakness may present as a dominant clinical manifestation and a major cause of disability and death.

Original publication




Journal article


Muscle Nerve

Publication Date





669 - 675


Adult, Aged, Base Sequence, Cell Line, DNA Mutational Analysis, Desmin, Female, Genetic Testing, Humans, Intermediate Filaments, Male, Middle Aged, Molecular Sequence Data, Muscle Fibers, Skeletal, Muscle Weakness, Muscular Diseases, Mutation, Proline, Protein Structure, Secondary, Respiratory Insufficiency, Respiratory Muscles, Respiratory Paralysis, Sequence Homology, Amino Acid