Histopathology of Skeletal Muscle in a Distal Motor Neuropathy Associated with a Mutant CCT5 Subunit: Clues for Future Developments to Improve Differential Diagnosis and Personalized Therapy

Abstract

Genetic chaperonopathies are rare but, because of misdiagnosis, there are probably more cases than those that are recorded in the literature and databases. This occurs because practitioners are generally unaware of the existence and/or the symptoms and signs of chaperonopathies. It is necessary to educate the medical community about these diseases and, with research, to unveil their mechanisms. The structure and functions of various chaperones in vitro have been studied, but information on the impact of mutant chaperones in humans, in vivo, is scarce. Here, we present a succinct review of the most salient abnormalities of skeletal muscle, based on our earlier report of a patient who carried a mutation in the chaperonin CCT5 subunit and suffered from a distal motor neuropathy of early onset. We discuss our results in relation to the very few other published pertinent reports we were able to find. A complex picture of multiple muscle-tissue abnormalities was evident, with signs of atrophy, apoptosis, and abnormally low levels and atypical distribution patterns of some components of muscle and the chaperone system. In-silico analysis predicts that the mutation affects CCT5 in a way that could interfere with the recognition and handling of substrate. Thus, it is possible that some of the abnormalities are the direct consequence of defective chaperoning, but others may be indirectly related to defective chaperoning or caused by other different pathogenic pathways. Biochemical, and molecular biologic and genetic analyses should now help in understanding the mechanisms underpinning the histologic abnormalities and, thus, provide clues to facilitate diagnosis and guide the development of therapeutic tools.

Keywords: CCT5 mutation; apical domain; chaperone system; chaperonopathies; desmin; distal neuropathies; human CCT; immunofluorescence; immunohistochemistry; molecular chaperone; molecular dynamics simulations; muscle pathology; protein aggregates; skeletal muscle.

Figure 1

Possible scenario in which the structure, muscles, or nerves may be primarily affected by the Leu224Val mutation in the CCT5 subunit, taking into consideration the absence of clinical or functional alterations of the patient’s heart. We did not find any cardiac alteration in our patient but, instead, we detected a decrease in the white matter in the central and peripheral nervous systems. Consequently, we hypothesize, as a basis for future research, a primary damage of neurons/glia in our patient, causing denervation of the skeletal muscle with its histopathological consequences.