Protein defects in neuromuscular diseases

Abstract

Muscular dystrophies are a heterogeneous group of genetically determined progressive disorders of the muscle with a primary or predominant involvement of the pelvic or shoulder girdle musculature. The clinical course is highly variable, ranging from severe congenital forms with rapid progression to milder forms with later onset and a slower course. In recent years, several proteins from the sarcolemmal muscle membrane (dystrophin, sarcoglycans, dysferlin, caveolin-3), from the extracellular matrix (a2-laminin, collagen VI), from the sarcomere (telethonin, myotilin, titin, nebulin), from the muscle cytosol (calpain 3, TRIM32), from the nucleus (emerin, lamin A/C, survival motor neuron protein), and from the glycosylation pathway (fukutin, fukutin-related protein) have been identified. Mutations in their respective genes are responsible for different forms of neuromuscular diseases. Protein analysis using Western blotting or immunohistochemistry with specific antibodies is of the utmost importance for the differential diagnosis and elucidation of the physiopathology of each genetic disorder involved. Recent molecular studies have shown clinical inter-and intra-familial variability in several genetic disorders highlighting the importance of other factors in determining phenotypic expression and the role of possible modifying genes and protein interactions. Developmental studies can help elucidate the mechanism of normal muscle formation and thus muscle regeneration. In the last fifteen years, our research has focused on muscle protein expression, localization and possible interactions in patients affected by different forms of muscular dystrophies. The main objective of this review is to summarize the most recent findings in the field and our own contribution.

Identification of three distinguishable phenotypes in golden retriever muscular dystrophy

“…The identification and classification of these three phenotypes may reflect important inter-and intra-familiar clinical variability, which is seen in DMD patients and which cannot be attributed to genetic factors (Vainzof and Zatz, 2003), but a correlation between the amount of dystrophin and the severity of the phenotype has been suggested by the cited authors. Sifringer et al (2004) suggested that an increase in some proteins such as casein kinase I, dynactin 3 light chain and the core-binding factor beta, which are involved in the regulation of the cell cycle, may be related to a milder phenotype.…”

“…Some patients may be able to walk throughout their lives. A patient is classified as having DMD when wheelchair-dependent before the age of 13, and as having BMD when able to walk beyond the age of 16 (Vainzof and Zatz, 2003). However, a recent clinical casebook described a boy without any signs of DMD (Dubowitz, 2006) but with confirmation of molecular findings.…”

Letter to the Editor Comments to the paper by Ambrósio CE, Fadel L, Gaiad TP, Martins DS, et al. [Identification of three distinguishable phenotypes in golden retriever muscular dystrophy (Genet. Mol. Res. 2009 Apr 7;8 (2): 389-396)]

“…-In the cited review from Vainzof and Zatz (2003), there are wrong interpretations. DMD patients DO NOT show important inter-and intrafamiliar clinical variability, as mentioned above.…”

“…DMD patients DO NOT show important inter-and intrafamiliar clinical variability, as mentioned above. In this review, Vainzof and Zatz (2003) commented about clinical inter-and intrafamilial variability in several other genetic disorders, including SOME other forms of muscular dystrophies, and highlighted the role of possible modifying genes and protein interactions in determining this phenotypic variability;…”

Caregivers’ sleep of Duchenne Muscular Dystrophy’s patients: a short review

“…After this phase, it follows a decline of the pulmonary function [13], and the respiratory failure is the cause of death in about 80% of the patients [14][15]. Survival goes until the third decade of life (about 25 years of age), mainly due to cardiac or respiratory failure [16]. Ventilation with the help of a non-invasive ventilatory support (NIV) minimizes the progression of the ventilatory insufficiency, improving therefore, the quality of life and life expectancy [17].…”