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Lookup NU author(s): Dr Julie Reichelt
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Mutations in the human myotilin gene may cause limb-girdle muscular dystrophy 1A and myofibrillar myopathy. Here, we describe a German patient with the clinically distinct disease phenotype of late adult onset distal anterior leg myopathy caused by a heterozygous S55F myotilin mutation. In addition to a thorough morphological and clinical analysis, we performed for the first time a protein chemical analysis and transient transfections. Morphological analysis revealed an inclusion body myopathy with myotilin- and desmin-positive aggregates. The clinical and pathological phenotype considerably overlaps with late onset distal anterior leg myopathy of the Markesbery-Griggs type. Interestingly, all three analyzed myotilin missense mutations (S55F, S60F and S60C) do not lead to gross changes in the total amount of myotilin or to aberrant posttranslational modifications in diseased muscle, as observed in a number of muscular dystrophies. Transiently transfected wild-type and S55F mutant myotilin similarly colocalised with actin-containing stress fibers in BHK-21 cells. Like the wild-type protein, mutated myotilin did not disrupt the endogenous desmin cytoskeleton or lead to pathological protein aggregation in these cells. This lack of an obvious dominant negative effect sharply contrasts to transfections with, for instance, the disease-causing A357P desmin mutant. In conclusion our data indicate that the disorganization of the extrasarcomeric cytoskeleton and the presence of desmin-positive aggregates are in fact late secondary events in the pathogenesis of primary myotilinopathies, rather than directly related. These findings suggest that unrelated molecular pathways may result in seemingly similar disease phenotypes at late disease stages.
Author(s): Fischer D, Clemen CS, Olive M, Ferrer I, Goudeau B, Roth U, Badorf P, Wattjes MP, Lutterbey G, Kral T, van der Ven PF, Furst DO, Vicart P, Goldfarb LG, Moza M, Carpen O, Reichelt J, Schroder R
Publication type: Article
Publication status: Published
Journal: Neuromuscular Disorders
Year: 2006
Volume: 16
Issue: 6
Pages: 361-367
ISSN (print): 0960-8966
ISSN (electronic): 1873-2364
Publisher: Elsevier Ltd
URL: http://dx.doi.org/10.1016/j.nmd.2006.03.007
DOI: 10.1016/j.nmd.2006.03.007
Notes: Case Reports Comparative Study Journal Article Research Support, Non-U.S. Gov't England Nmd
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