The Pathogenesis and Therapy of Muscular Dystrophies

Abstract

Current molecular genomic approaches to human genetic disorders have led to an explosion in the identification of the genes and their encoded proteins responsible for these disorders. The identification of the gene altered by mutations in Duchenne and Becker muscular dystrophy was one of the earliest examples of this paradigm. The nearly 30 years of research partly outlined here exemplifies the road that similar current gene discovery protocols will be expected to travel, albeit much more rapidly owing to improved diagnosis of genetic disorders and an understanding of the spectrum of mutations thought to cause them. The identification of the protein dystrophin has led to a new understanding of the muscle cell membrane and the proteins involved in membrane stability, as well as new candidate genes for additional forms of muscular dystrophy. Animal models identified with naturally occurring mutations and developed by genetic manipulation have furthered the understanding of disease progression and underlying pathology. The biochemistry and molecular analysis of patient samples have led to the different dystrophin-dependent and -independent therapies that are currently close to or in human clinical trials. The lessons learned from decades of research on dystrophin have benefited the field of human genetics.

Muscular dystrophy in PTFR/cavin-1 null mice

“…Muscular dystrophies (MDs) are a group of diseases of variable severity that are caused by mutations in a relatively large number of different genes, which cause progressive loss of muscle function (1). Most of the mutated genes causing MDs are involved in sarcolemmal functions, the maintenance of membrane integrity, and/or communication with the extracellular matrix (2).…”

Understanding molecular mechanisms in propionic acidemia and investigated therapeutic strategies

“…The most widely used ones for splicing manipulation are phosphorothioates with 2'-O-modifications of the ribose residue (2'-O-methyl and 2'-O-methoxyethyl) and phosphordiamidate morpholino oligonucleotides (PMOs). In Duchenne muscular dystrophy, 2OMePS and PMOs are currently in clinical trials with promising results [85].…”

Deficiency in Kelch protein Klhl31 causes congenital myopathy in mice

“…Additionally, protein aggregates, centralized nuclei, and a paucity of sarcomeric proteins could easily be detected in longitudinal sections by H&E staining of quadriceps (Supplemental Figure 3D). Membrane proteins involved in muscular dystrophies (15,16), however, were unperturbed (Supplemental Figure 4).…”