Different early pathogenesis in myotilinopathy compared to primary desminopathy

被引:20
作者
Fischer, Dirk
Clemen, Christoph S.
Olive, Montse
Ferrer, Isidro
Goudeau, Bertrand
Roth, Udo
Badorf, Petra
Wattjes, Mike P.
Lutterbey, Goetz
Kral, Thomas
van der Ven, Peter F. M.
Fuerst, Dieter O.
Vicart, Patrick
Goldfarb, Lev G.
Moza, Monica
Carpen, Olli
Reichelt, Julia
Schroeder, Rolf
机构
[1] Univ Bonn, Dept Neurol, Muskellab, D-53105 Bonn, Germany
[2] Univ Paris 06, CNRS, UMR 7000, Paris, France
[3] Univ Bonn, Dept Mol Cell Biol, D-5300 Bonn, Germany
[4] Univ Cologne, Fac Med, Ctr Biochem, Inst Biochem 1, Cologne, Germany
[5] Hosp Llobregat, Inst Neuropatol, IDIBELL, Barcelona, Spain
[6] Univ Cologne, Fac Med, Ctr Mol Med Cologne, Cologne, Germany
[7] Univ Bonn, Dept Radiol, D-5300 Bonn, Germany
[8] Univ Bonn, Dept Neurosurg, D-5300 Bonn, Germany
[9] Univ Paris 07, UFR Biochem, Paris, France
[10] NINDS, Clin Neurogenet Unit, NIH, Bethesda, MD 20892 USA
[11] Univ Helsinki, Dept Pathol, Helsinki, Finland
[12] Univ Helsinki, Neurosci Program, Helsinki, Finland
[13] Univ Helsinki, Cent Hosp, Helsinki, Finland
[14] Turku Univ, Cent Hosp, FIN-20520 Turku, Finland
[15] Univ Turku, Dept Pathol, Turku, Finland
关键词
myotilin; titin; limb-girdle muscular dystrophy; distal myopathy; tibial muscular dystrophy; myofibrillar myopathy; inclusion body myopathy; desmin;
D O I
10.1016/j.nmd.2006.03.007
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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. (C) 2006 Elsevier B.V. All rights reserved.
引用
收藏
页码:361 / 367
页数:7
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