The Pathogenesis and Therapies of Striated Muscle Laminopathies

Abstract

Emery-Dreifuss muscular dystrophy (EDMD) is a genetic condition characterized by early contractures, skeletal muscle weakness, and cardiomyopathy. During the last 20 years, various genetic approaches led to the identification of causal genes of EDMD and related disorders, all encoding nuclear envelope proteins. By their respective localization either at the inner nuclear membrane or the outer nuclear membrane, these proteins interact with each other and establish a connection between the nucleus and the cytoskeleton. Beside this physical link, these proteins are also involved in mechanotransduction, responding to environmental cues, such as increased tension of the cytoskeleton, by the activation or repression of specific sets of genes. This ability of cells to adapt to environmental conditions is altered in EDMD. Increased knowledge on the pathophysiology of EDMD has led to the development of drug or gene therapies that have been tested on mouse models. This review proposed an overview of the functions played by the different proteins involved in EDMD and related disorders and the current therapeutic approaches tested so far.

The mutation of Transportin 3 gene that causes limb girdle muscular dystrophy 1F induces protection against HIV-1 infection

“…Apart from these preliminary results, the mechanism by which TNPO3 mutation affects its function and causes LGMD1F remains undetermined. Interestingly, other rare muscular diseases known as laminopathies are related to changes in the nuclear lamin architecture, a fibrous structure located below the nuclear membrane which functions include among others the regulation of the nuclear transport [46,47]. Besides, other muscle diseases like myotonic dystrophies are due to mutations in splicing factors.…”

Rare BANF1 Alleles and Relatively Frequent EMD Alleles Including ‘Healthy Lipid’ Emerin p.D149H in the ExAC Cohort

“…The emerin p.D149H lipid phenotype raises important questions. What do these ‘healthy’ lipid traits imply about the normal roles of emerin in striated muscle (Brull et al, 2018), or other tissues? Is this emerin phenotype related to the immobilization of BANF1 at the nuclear lamina in response to fasting in Caenorhabditis elegans intestinal cells (Bar et al, 2014)?…”

Need for NAD+: Focus on Striated Muscle Laminopathies

“…Since the first description of LMNA mutations associated with Emery–Dreifuss muscular dystrophy (EDMD) through positional cloning in 1999 [ 4 ], the improvement of genetic strategies allowed the identification of other LMNA variants (reviewed by [ 5 ]). To date, more than 10 human clinical entities have been attributed to LMNA mutations.…”

“…The mechanisms by which mutations in LMNA, the gene responsible for the autosomal form of EDMD, cause tissue-specific disorders are poorly understood. Research on striated muscle laminopathies in recent years has provided novel perspectives on the role of the nuclear lamina and has shed light on the pathological consequences of altered nuclear lamina [ 5 ]. Although progresses have been made to identify genes causing the disease and to decipher pathological mechanisms, there is currently no curative treatment for these diseases.…”