PubMed · 16006808
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William Bradlyn Laskin, Rameez Alasadi, Daina Variakojis. 2005. Splenic hamartoma.. https://pubmed.ncbi.nlm.nih.gov/16006808/
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Most mutations of desmin that cause severe autosomal dominant forms of myofibrillar myopathy are point mutations and locate in the central alpha-helical coiled-coil rod domain. Recently, two in-frame deletions of one and three amino acids, respectively, in the alpha-helix have been described and discussed to drastically interfere with the architecture of the desmin dimer and possibly also the formation of tetramers and higher order complexes [Kaminska, A., Strelkov, S.V., Goudeau, B., Olive, M., Dagvadorj, A., Fidzianska, A., Simon-Casteras, M., Shatunov, A., Dalakas, M.C., Ferrer, I., Kwiecinski, H., Vicart, P., Goldfarb, L.G., 2004. Small deletions disturb desmin architecture leading to breakdown of muscle cells and development of skeletal or cardioskeletal myopathy. Hum. Genet. 114, 306-313.]. Therefore, it was proposed that they may poison intermediate filament (IF) assembly. We have now recombinantly synthesized both mutant proteins and subjected them to comprehensive in vitro assembly experiments. While exhibiting assembly defects when analyzed on their own, both one-to-one mixtures of the respective mutant protein with wild type desmin facilitated proper filament formation. Transient transfection studies complemented this fundamental finding by demonstrating that wild type desmin is also rescuing these assembly defects in vivo. In summary, our findings strongly question the previous hypothesis that it is assembly incompetence due to molecular rearrangements caused by the mutations, which triggers the development of disease. As an alternative, we propose that these mutations cause subtle age-dependent structural alterations of desmin IFs that eventually lead to disease.
Mesenchymal hamartoma is an uncommon cystic mass of the liver which occurs primarily in children. There are a few reports of its occurrence in adulthood. Here, we present two cases in female patients, 54 and 51 years old. Radiological examinations in both patients showed multiple cystic lesions in the liver. Surgically, total cystectomy was performed in the first patient, while an unroofing procedure was done in the second patient (due to misdiagnosis of the lesion as a simple cyst of the liver). On microscopic examinations of the lesion in each patient, a multilocular cyst was observed, lined by flattened epithelium and surrounded by a mesenchymal component composed of mature connective tissue, arterial and venous vascular structures, peripheral nerve bundles, and ductal structures. An immunohistochemical panel consisting of desmin, smooth-muscle actin, S-100, vimentin, CD34, carcinoembryonic antigen, pancytokeratin, cytokeratin 7, cytokeratin 8, cytokeratin 17, cytokeratin 18, cytokeratin 19, and cytokeratin 20 was applied to paraffin sections. Immunoreactivity for cytokeratin 7 and cytokeratin 19 was observed in cystic epithelium and ductal structures. Focal and patchy desmin immunoreactivity was observed in connective tissue. S-100 was positive only in peripheral nerve bundles. In conclusion, mesenchymal hamartoma of the liver in adulthood is a localized tumoral abnormality that precedes birth, and which has delayed clinical presentation. These lesions seems to be related to a maturation process. During this period of maturation, immature edematous stroma rich in mucopolysaccharides may convert to mature paucicellular hyalinized connective tissue. This maturation process may be also related to loss of premalignant potential of these tumors.
We have investigated the co-assembly properties of the intermediate filament (IF) proteins vimentin and desmin. First, the soluble complexes formed by both proteins separately in 5 mM Tris-HCl, pH 8.4, were characterized by analytical ultracentrifugation. In both cases, s-values of around 5 S were obtained corresponding to the formation of tetramers. However, at pH 7.5 and in the presence of 1 mM EDTA, both proteins behaved quite differently; whereas vimentin sedimented at 7.2 S, desmin assembled into much larger complexes of about 13 S. A mixture of equimolar amounts of vimentin and desmin in 8 M urea yielded, after reconstitution into 5 mM Tris-HCl, pH 7.5, and 1 mM EDTA, complexes exhibiting a sharp peak at 10.9 S. This intermediate s-value indicated that co-assembly into a distinct new set of complexes had occurred. As judged by electron microscopy and viscometry, these mixtures assembled into IFs with characteristics similar to those of pure vimentin and desmin. Furthermore, when vimentin and desmin tetramers were mixed in 5 mM Tris-HCl, pH 8.4, and subsequently subjected to IF assembly conditions, again "hybrid" filaments were obtained. Most interestingly, after 10 min of assembly, mass-per-length (MPL) measurements by scanning transmission electron microscopy yielded IFs with an MPL-peak value of 36 +/- 5 kDa/nm, hence closer to that of vimentin IFs (33 +/- 4 kDa/nm) than to that of desmin IFs (48 +/- 8 kDa/nm). Finally, when unit length-filaments (ULF) of vimentin and desmin were mixed and assembled further, the diameters of individual mature IFs formed exhibited a significantly higher degree of width inhomogeneity along their length than vimentin and desmin IFs as might be expected for a modular mode of assembly. Last but not least, atomic force microscopy provided further direct evidence that desmin IFs are able to fuse end-to-end with vimentin IFs. In summary, we have shown that vimentin and desmin are able to co-assemble at the dimer, tetramer, ULF and even the mature IF level.