Abstract
Desmin (DES) mutations have been recognized as a cause of desmin-related myopathy (OMIM 601419), or desminopathy, a disease characterized by progressive limb muscle weakness and accumulation of desmin-reactive granular aggregates in the myofibers. We have studied three families with skeletal or cardioskeletal myopathy caused by small in-frame deletions in the desmin gene. The newly identified in-frame deletions E359_S361del and N366del alter the heptad periodicity within a critical 2B coiled-coil segment. Structural analysis reveals that the E359_S361 deletion introduces a second stutter immediately downstream of the naturally occurring stutter, thus doubling the extent of the local coiled-coil unwinding. The N366del mutation converts the wild-type stutter into a different type of discontinuity, a stammer. A stammer, as opposed to a stutter, is expected to cause an extra overwinding of the coiled-coil. These mutations alter the coiled-coil geometry in specific ways leading to fatal damage to desmin filament assembly. Expression studies in two cell lines confirm the inability of desmin molecules with this changed architecture to polymerize into a functional filamentous network. This study provides insights into molecular pathogenetic mechanisms of desmin mutation-associated skeletal and cardioskeletal myopathy.
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Acknowledgements
The authors are grateful to the members of the affected families for their enthusiastic participation in this study. Dr. Strelkov acknowledges support from the Swiss National Science Foundation and the M.E. Müller Foundation of Switzerland. The work of Drs. Goudeau, Simon-Casteras, and Vicart was supported by a grant from the Association Française contre les Myopathies (AFM). Drs. Olivé and Ferrer were recipients of FIS 02-0005 and SAF2001-4681-E grants and were generously supported by the Centro Vasco Txoco Lagun-Artea.
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Electronic database information: nucleotide and amino acid sequence data are available in the GenBank database (http://www.ncbi.nlm.nih.gov/Genbank) under accession nos. AY114212 for E359_S361del and AF21879 for N366del mutations
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Kaminska, A., Strelkov, S.V., Goudeau, B. et al. Small deletions disturb desmin architecture leading to breakdown of muscle cells and development of skeletal or cardioskeletal myopathy. Hum Genet 114, 306–313 (2004). https://doi.org/10.1007/s00439-003-1057-7
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DOI: https://doi.org/10.1007/s00439-003-1057-7