Gene-related protein surplus myopathies

Numerous muscular dystrophies, such as dystrophinopathies, sarcoglycanopath ies, and emerino- and laminopathies, are marked by the absence or reduction of mutant transsarcolemmal or nuclear proteins. In addition to these recen tly identified minus-proteinopathies, there are a growing number of plus-pr oteinopathies among neuromuscular disorders marked by a surplus or excess o f endogenous proteins within muscle fibers of different, i.e., nontranssarc olemmal and nonnuclear types. These proteins are often filamentous; for exa mple, desmin and actin accrue in respective desmin-related myopathies, amon g which are entities marked by mutant desmin, true desminopathies, and acti nopathy, the latter often seen as a subgroup in nemaline myopathies. Desmin -related myopathies consist largely of those marked by desmin-containing in clusions and those characterized by desmin-containing granulofilamentous ma terial. When mutations in the desmin gene can be identified, the mutant des min is thought to form the major myopathological lesion. Together with desm in, other proteins often accumulate. The spectrum of these proteins is quit e diverse and encompasses such proteins as dystrophin, nestin, vimentin, al pha B-crystallin, ubiquitin, amyloid precursor protein, and beta-amyloid ep itopes, as well as gelsolin and alpha(1)-antichymotrypsin. Among these asso ciated proteins, one, alpha B-crystallin, has been found mutant in one larg e family, justifying the term alpha B-crystallinopathy as a separate condit ion among the desmin-related myopathies. Other proteins accruing with desmi n have not yet been identified as mutant in desmin-related myopathies. Muta tions in the desmin gene entail missense mutations and small deletions. The formation of mutant actin may lead to aggregates of actin filaments which may or may not be associated with formation of sarcoplasmic and/or intranuc lear nemaline bodies. A considerable number of missense mutations in the sa rcomeric actin gene ACTA1 have been discovered in patients with nemaline my opathy and also in a few patients without myopathological evidence of nemal ine bodies in biopsied skeletal muscle fibres. Apart from alpha B-crystalli n, no other proteins coaggregating with actin in actin filament aggregates of actinopathy or the actin mutation type of nemaline myopathy have so far been identified. Two further candidates for protein surplus myopathies are hyaline body myopathy, which is marked by accumulation of granular nonfilam entous material within muscle fibers that is rich in myosin and adenosine t riphosphatase activities, and hereditary inclusion body myopathies, which a re marked by accumulation of tubulofilaments similar to the helical filamen ts of Alzheimer neurofibrillary tangles. These tubulofilaments consist of d iverse proteins as well, though no mutant protein has yet been discovered. So far, no genes responsible for familial hyaline body and hereditary inclu sion body myopathies have been identified. The discovery of mutant proteins , desmin, alpha B-crystallin, and actin, as components of surplus or excess proteins accumulating in muscle fibers in certain neuromuscular conditions is responsible for the recent emergence of this new concept of gene-relate d protein surplus myopathies. (C) 2000 Academic Press.