Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dystroglycan (DG) is a highly expressed extracellular matrix receptor that is linked to the cytoskeleton in skeletal muscle. DG is critical for the function of skeletal muscle, and muscle with primary defects in the expression and/or function of DG throughout development has many pathological features and a severe muscular dystrophy phenotype. In addition, reduction in DG at the sarcolemma is a common feature in muscle biopsies from patients with various types of muscular dystrophy. However, the consequence of disrupting DG in mature muscle is not known. Here, we investigated muscles of transgenic mice several months after genetic knockdown of DG at maturity. In our study, an increase in susceptibility to contraction-induced injury was the first pathological feature observed after the levels of DG at the sarcolemma were reduced. The contraction-induced injury was not accompanied by increased necrosis, excitation-contraction uncoupling, or fragility of the sarcolemma. Rather, disruption of the sarcomeric cytoskeleton was evident as reduced passive tension and decreased titin immunostaining. These results reveal a role for DG in maintaining the stability of the sarcomeric cytoskeleton during contraction and provide mechanistic insight into the cause of the reduction in strength that occurs in muscular dystrophy after lengthening contractions.
 ...
PMID:Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle. 2762 24

Multiminicore disease is a myopathy that is pathologically characterized by the presence of multiple areas of small, short, and poorly delineated zones of sarcomeric disorganization lacking mitochondria (minicores) that can be observed in both type 1 and type 2 fibers. Most cases of multiminicore disease typically present with early-onset axial weakness, respiratory insufficiency, scoliosis, and rigid spine. There is no correlation between the frequency of minicores and clinical severity. Multiminicore disease is genetically heterogeneous and can result from recessive or dominant mutations. Genetic testing is needed to establish the precise diagnosis and provide overall prognosis. Here we report a 23-year-old woman with respiratory failure, distal joint hyper-laxity, scoliosis and rigid spine due to multiminicore disease caused by a novel compound heterozygous mutation in the selenoprotein N1-encoding gene (SELN). The preserved ambulation into adulthood and normal creatinine kinase (CK) favor the diagnosis of congenital myopathy over congenital muscular dystrophy (CMD). However, the nonspecific myopathic histopathological changes and extremely rare minicore-like structures can make it challenging to differentiate between SELN-myopathy and congenital muscular dystrophies, such as Ullrich or lamin A/C-CMD.
 ...
PMID:Congenital myopathy with a novel SELN missense mutation and the challenge to differentiate it from congenital muscular dystrophy. 3061 14

Titin, encoded by the gene TTN, is the largest human protein, and plays central roles in sarcomeric structures and functions in skeletal and cardiac muscles. Mutations of TTN are causally related to specific types of muscular dystrophies and cardiomyopathies. A developed methodology of next generation sequencing has recently led to the identification of novel TTN mutations in such diseases. The clinical significance of titin is now emerging as a target for genetic strategies. Titin-related muscular dystrophies include tibial muscular dystrophy, limb-girdle muscular dystrophy, Emery-Dreifuss muscular dystrophy, hereditary myopathy with early respiratory failure, central core myopathy, centronuclear myopathies, and Salih myopathy. Truncation mutations of TTN have been identified as the most frequent genetic cause of dilated cardiomyopathy. In this review article, we highlight the role of titin and impact of TTN mutations in the pathogenesis of muscular dystrophies and cardiomyopathies. Recently, a novel sensitive sandwich enzyme-linked immunosorbent assay (ELISA) for the detection of the urinary titin N-terminal fragments (U-TN) has been established. We discuss the clinical significance of U-TN in the diagnosis of muscular dystrophies and differential diagnosis of cardiomyopathies, as well as risk stratification in dilated cardiomyopathy.
 ...
PMID:Titin in muscular dystrophy and cardiomyopathy: Urinary titin as a novel marker. 3095 43

Since its belated discovery, our understanding of the giant protein titin has grown exponentially from its humble beginning as a sarcomeric scaffold to recent recognition of its critical mechanical and signaling functions in active muscle. One uniquely useful model to unravel titin's functions, muscular dystrophy with myositis (mdm), arose spontaneously in mice as a transposon-like LINE repeat insertion that results in a small deletion in the N2A region of titin. This small deletion profoundly affects hypertrophic signaling and muscle mechanics, thereby providing insights into the function of this specific region and the consequences of its dysfunction. The impact of this mutation is profound, affecting diverse aspects of the phenotype including muscle mechanics, developmental hypertrophy, and thermoregulation. In this review, we explore accumulating evidence that points to the N2A region of titin as a dynamic "switch" that is critical for both mechanical and signaling functions in skeletal muscle. Calcium-dependent binding of N2A titin to actin filaments triggers a cascade of changes in titin that affect mechanical properties such as elastic energy storage and return, as well as hypertrophic signaling. The mdm phenotype also points to the existence of as yet unidentified signaling pathways for muscle hypertrophy and thermoregulation, likely involving titin's PEVK region as well as the N2A signalosome.
 ...
PMID:N2A Titin: Signaling Hub and Mechanical Switch in Skeletal Muscle. 3249 76


<< Previous 1 2 3 4