Abstract
Since the discovery of the inner nuclear transmembrane protein emerin in the early 1990s, nuclear envelope (NE) components and related involvement in nuclei integrity and functionality have been highly investigated. The NE is composed of two distinct lipid bilayers described as the inner (INM) and outer (ONM) nuclear membrane. NE proteins can be specifically “integrated” in the INM (such as emerin and SUN proteins) or in the ONM such as nesprins. Additionally, flanked to the INM, the nuclear lamina, a proteinaceous meshwork mainly composed of lamins A and C completes NE composition. This network of proteins physically interplays to guarantee NE integrity and most importantly, shape the bridge between cytoplasmic cytoskeletons networks (such as microtubules and actin) and the genome, through the anchorage to the heterochromatin. The essential network driving the connection of nucleoskeleton with cytoskeleton takes place in the perinuclear space (the space between ONM and INM) with the contribution of the LINC complex (for Linker of Nucleoskeleton to Cytoskeleton), hosting KASH and SUN proteins interactions. This close interplay between compartments has been related to diverse functions from nuclear integrity, activity and positioning through mechanotransduction pathways. At the same time, mutations in NE components genes coding for proteins such as lamins or nesprins, had been associated with a wide range of congenital diseases including cardiac and muscular diseases. Although most of these NE associated proteins are ubiquitously expressed, a large number of tissue-specific disorders have been associated with diverse pathogenic mutations. Thus, diagnosis and molecular explanation of this group of diseases, commonly called “nuclear envelopathies,” is currently challenging. This review aims, first, to give a better understanding of diverse functions of the LINC complex components, from the point of view of lamins and nesprins. Second, to summarize human congenital diseases with a special focus on muscle and heart abnormalities, caused by mutations in genes coding for these two types of NE associated proteins.
Highlights
The Nuclear Envelope (NE) is composed of two distinct lipid bilayers so called inner (INM) and outer (ONM) nuclear membrane
In the perinuclear space, proteins localized at the outer nuclear membrane (ONM) and containing Klarsicht/Anc-1/Syne Homology (KASH) domains (Klarsicht/Anc-1/Syne homology) with proteins localized at the inner nuclear membrane (INM) and containing SUN domains (Sad1/UNC-84 homology) (Tapley and Starr, 2013)
Laminopathies include a group of diseases with a predominant skeletal muscle and/or heart involvement, such as the autosomal dominant form of emery-dreifuss muscular dystrophy (EDMD) (EDMD-2 or Autosomal-Dominant Emery-Dreifuss Muscular Dystrophy (AD-EDMD)), the autosomal recessive form of EDMD (EDMD-3), a dilated cardiomyopathy phenotype associated with conduction defects (DCM-CD), Congenital Muscular Dystrophy (L-congenital muscular dystrophy (CMD) or LMNA-CMD) and Limb-Girdle Muscular Dystrophy 1B (LGMD1B) (Bönnemann et al, 2014)
Summary
The Nuclear Envelope (NE) is composed of two distinct lipid bilayers so called inner (INM) and outer (ONM) nuclear membrane. C-terminus domain is located in the perinuclear space and interacts with nesprins, which are embedded in the ONM (Padmakumar et al, 2005; Crisp et al, 2006; Haque et al, 2006; Ketema et al, 2007; Horn et al, 2013) This LINC complex play a role in diverse specialized cellular activities such as nuclear morphology maintenance, nuclear positioning, genes expression and cell signaling (Crisp et al, 2006; Lombardi and Lammerding, 2011; Mellad et al, 2011; Stroud et al, 2014). We will recapitulate known muscular and cardiac abnormalities induced by mutations in those genes and will discuss our recent advances in related pathogenesis
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