Congenital myopathies at their molecular dawning

Abstract

The introduction and application of molecular techniques have commenced to influence and alter the nosology of congenital myopathies. Long-known entities such as nemaline myopathies, core diseases, and desmin-related myopathies have now been found to be caused by unequivocal mutations. Several of these mutations and their genes have been identified by analyzing aggregates of proteins within muscle fibers as a morphological hallmark as in desminopathy and actinopathy, the latter a subtype among the nemaline myopathies. Immunohistochemistry has played a crucial role in recognizing this new group of protein aggregate myopathies within the spectrum of congenital myopathies. It is to be expected that other congenital myopathies marked by inclusion bodies may turn out to be such protein aggregate myopathies, depending on analysis of individual proteins within these protein aggregates and their association with putative gene mutations.

Desmin Aggregate Formation by R120G αB-Crystallin Is Caused by Altered Filament Interactions and Is Dependent upon Network Status in Cells

“…Bars, 20 m. Quantification of desmin network organizations in transfected cells is shown in wild-type ␣B-crystallin (Selcen and Engel, 2003), again suggestive of a compromised protein degradation system. Indeed, the protein aggregates containing the desmin and ␣B-crystallin were not ubiquitin labeled (Selcen and Engel, 2003), which is unusual compared with other myopathies (Goebel and Warlo, 2000;Goebel, 2003). Satellite cells isolated from patients with the R120G ␣B-crystallin mutation were also more susceptible to oxidative stress (Nedellec et al, 2002) symptomatic of a compromised stress response.…”

“…DRMs caused by mutations in either the desmin or ␣B-crystallin gene are inherited neuromuscular disorders that are characterized by the accumulation of aggregates containing desmin and ␣B-crystallin (Vicart et al, 1998;Goebel and Warlo, 2001;Fischer et al, 2002;Goebel, 2003). Despite this direct physical association between desmin and ␣B-crystallin in patients with myopathy, analysis of the effects of R120G ␣B-crystallin in a mouse model (Wang et al, 2001) and a tissue culture model (Chavez Zobel et al, 2003) suggested that there was not a direct interaction between desmin and ␣B-crystallin.…”

“…Aggregates of desmin and ␣B-crystallin typify the histopathological feature of the DRMs (Goebel and Warlo, 2000;Fischer et al, 2002;Goebel, 2003), and these would accompany and exacerbate compromised protein degradation in muscle cells. The compromised turnover of misfolded and/or damaged proteins would be an additional stress induced by the ␣B-crystallin mutations, which could either trigger or propagate the developing myopathy.…”

Miopatia por corpos esferóides: relato de caso

“…Goebel e col. observaram um padrão autossômico dominante em quatro gerações sucessivas 4 , embora já tenham sido relatados casos esporádicos e de herança autossômi-ca recessiva em caso de pais consangüíneos 7,13 .…”

A cell culture system for the induction of Mallory bodies: Mallory bodies and aggresomes represent different types of inclusion bodies

“…MB subtype III was characterized by the absence of a well-deWned Wlamentous structure and the presence of highly electron dense granular or homogeneous inclusions, which resemble aggresomes (Johnston et al 1998;Garcia-Mata et al 1999;Kopito and Sitia 2000). Aggresomes are cytoplasmic inclusion bodies observed in several non-hepatic diseases such as in some myopathies (Goebel 2003), in Alexander disease (Hagemann et al 2006), and in neurodegenerative diseases including Alzheimer and Parkinson disease as well as in amyotrophic lateral sclerosis (Cairns et al 2004). They are formed when the proteolytic capacity of the proteasome is exhausted and misfolded proteins aggregate in the cytosol (Johnston et al 1998;Garcia-Mata et al 1999;Kopito and Sitia 2000).…”