title: Different early pathogenesis in myotilinopathy compared to primary desminopathy.
abstract: 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.
authors: Muskellabor, Department of Neurology, University of Bonn, Bonn, Germany. dirk.fischer@ukb.uni-bonn.de
authors: Dirk
authors: D
authors: Fischer
authors: Christoph S
authors: CS
authors: Clemen
authors: Montse
authors: M
authors: Olivé
authors: Isidro
authors: I
authors: Ferrer
authors: Bertrand
authors: B
authors: Goudeau
authors: Udo
authors: U
authors: Roth
authors: Petra
authors: P
authors: Badorf
authors: Mike P
authors: MP
authors: Wattjes
authors: Götz
authors: G
authors: Lutterbey
authors: Thomas
authors: T
authors: Kral
authors: Peter F M
authors: PF
authors: van der Ven
authors: Dieter O
authors: DO
authors: Fürst
authors: Patrick
authors: P
authors: Vicart
authors: Lev G
authors: LG
authors: Goldfarb
authors: Monica
authors: M
authors: Moza
authors: Olli
authors: O
authors: Carpen
authors: Julia
authors: J
authors: Reichelt
authors: Rolf
authors: R
authors: Schröder