Nuclear envelopathies: a complex LINC between nuclear envelope and pathology

Abstract

Since the identification of the first disease causing mutation in the gene coding for emerin, a transmembrane protein of the inner nuclear membrane, hundreds of mutations and variants have been found in genes encoding for nuclear envelope components. These proteins can be part of the inner nuclear membrane (INM), such as emerin or SUN proteins, outer nuclear membrane (ONM), such as Nesprins, or the nuclear lamina, such as lamins A and C. However, they physically interact with each other to insure the nuclear envelope integrity and mediate the interactions of the nuclear envelope with both the genome, on the inner side, and the cytoskeleton, on the outer side. The core of this complex, called LINC (LInker of Nucleoskeleton to Cytoskeleton) is composed of KASH and SUN homology domain proteins. SUN proteins are INM proteins which interact with lamins by their N-terminal domain and with the KASH domain of nesprins located in the ONM by their C-terminal domain.Although most of these proteins are ubiquitously expressed, their mutations have been associated with a large number of clinically unrelated pathologies affecting specific tissues. Moreover, variants in SUN proteins have been found to modulate the severity of diseases induced by mutations in other LINC components or interactors. For these reasons, the diagnosis and the identification of the molecular explanation of “nuclear envelopathies” is currently challenging.The aim of this review is to summarize the human diseases caused by mutations in genes coding for INM proteins, nuclear lamina, and ONM proteins, and to discuss their potential physiopathological mechanisms that could explain the large spectrum of observed symptoms.

The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity

“…In cells with reduced nuclear import, we observed cytoplasmic lamin accumulation, suggesting that relatively high lamin import kinetics are necessary to avoid cytoplasmic aggregation. These lamin aggregates could be relevant to disease states where nuclear import is compromised [91][92][93][94][95], laminopathies [96][97][98][99][100][101][102], or cellular stress [103]. ELYS is a multifunctional protein which has been shown to interact with chromatin, enhancers, and promoters [53, 104,105].…”

In vivoimaging of myonuclei during spontaneous muscle contraction reveals non-uniform nuclear mechanical dynamics inNesprin/klarmutants

“…A partial explanation for this may be our previous finding that Troponin C levels decreased at the transcription, mRNA, and protein levels in Nesprin/klar mutants (Wang et al, 2018). Aberrant muscle contraction has been also described in human muscular dystrophies associated with mutations in the LINC complex (Janin et al, 2017;Méjat and Misteli, 2010).…”

Lamin A/C negatively regulated by miR‐124‐3p modulates apoptosis of vascular smooth muscle cells during cyclic stretch application in rats

“…Lamins are type V intermediate filament proteins that form the nuclear lamina, a filamentous network underlying the inner nuclear membrane of eukaryotic cells . Mutation, aberrant splicing and abnormal expression of lamin A/C, the nuclear A‐type lamins, will lead to the disruption of various crucial cellular functions and result in a number of devastating diseases.…”

“…Lamins are type V intermediate filament proteins that form the nuclear lamina, a filamentous network underlying the inner nuclear membrane of eukaryotic cells. 30 Mutation, 31 aberrant splicing 32 and abnormal expression 33 of lamin A/C, the nuclear A-type lamins, will lead to the disruption of various crucial cellular functions and result in a number of devastating diseases. For example, in the cardiovascular system, mutation of lamin A/C caused by Lmna mutations participates in up to 10% of dilated cardiomyopathies (DCMs) and underlies a spectrum of other diseases including muscular dystrophy, lipodystrophy and acrogeria syndromes.…”