Intermediate Filament Diseases: Desminopathy

Abstract

Desminopathy is one of the most common intermediate filament human disorders associated with mutations in closely interacting proteins, desmin and alphaB-crystallin. The inheritance pattern in familial desminopathy is characterized as autosomal dominant or autosomal recessive, but many cases have no family history. At least some and likely most sporadic desminopathy cases are associated with de novo DES mutations. The age of disease onset and rate of progression may vary depending on the type of inheritance and location of the causative mutation. Typically, the illness presents with lower and later upper limb muscle weakness slowly spreading to involve truncal, neckflexor, facial and bulbar muscles. Skeletal myopathy is often combined with cardiomyopathy manifested by conduction blocks, arrhythmias and chronic heart failure resulting in premature sudden death. Respiratory muscle weakness is a major complication in some patients. Sections of the affected skeletal and cardiac muscles show abnormal fibre areas containing chimeric aggregates consisting of desmin and other cytoskeletal proteins. Various DES gene mutations: point mutations, an insertion, small in-frame deletions and a larger exon-skipping deletion, have been identified in desminopathy patients. The majority of these mutations are located in conserved alpha-helical segments, but additional mutations have recently been identified in the tail domain. Filament and network assembly studies indicate that most but not all disease-causing mutations make desmin assembly-incompetent and able to disrupt a pre-existing filamentous network in dominant-negative fashion. AlphaBcrystallin serves as a chaperone for desmin preventing its aggregation under various forms of stress; mutant CRYAB causes cardiac and skeletal myopathies identical to those resulting from DES mutations.

Expression of Intermediate Filaments in the Development of Genioglossus Muscle

“…Vimentin is specific in mesenchymal cells and considered to be deeply involved in building tissues. In contrast, desmin is considered to be specifically expressed in muscle but not in premature tissues 5,7) . The expression of vimentin at E11 in which there was no separation of the mandible and the tongue indicates that vimentin is important in the development of these tissues.…”

“…The role of desmin in repair and retention of muscle tissue has been established 4,5) . Expression of desmin at the junction of nerve and muscle during the development of muscle and tendons in skeletal muscle has been known 6) .…”

Muscle Fibers Lacking Desmin in the Extraocular Muscles: A Paradigm Shift

“…Desmin is a crucial cytoskeletal protein in the vast majority of muscle ibers, and it is proposed to be fundamental for maintenance of iber integrity, force transduction, and mechanochemical signaling as it links the contractile elements both to the sarcolemma and to the nuclear membrane [14,21]. However, it is diicult to speculate on possible physiological consequences of the absence of desmin on these slow tonic muscle ibers of the human extraocular muscles, and further studies correlating structural properties and physiological behavior are required.…”

Myofibrillar Myopathies and the Z-Disk Associated Proteins

“…Interestingly, no mutations in domain 2A have been reported to date and m o r e t h a n 5 0 % o f r e p o r t e d D e s m i n m u t a t i o n s a r e i n t h e 2 B d o m a i n [ 3 5 ] . A l t h o u g h a correlation between the domain mutated and the clinical features of the patients/carriers has been suggested (reviewed in [35]), when the clinical features are analysed in more detail the only correlation that appears to be maintained is the predominance of skeletal muscle defects in patients with mutations in the 2B domain (Table 1 and Table 2). Mutations are coloured accordingly to the disease classification.…”