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.

Keywords: EMD; LAP2; LINC complex; LMNA; Lamins a/C; Nesprins; Nuclear envelope; Sun; ZMPSTE24.

Fig. 1

The LINC complex, its interactors, and associated diseases. Schematic representation of the different nuclear envelope components and their interactions. The pathologies associated with mutations in the related genes are indicated in the corresponding boxes. LINC complex components (SUN proteins in green and Nesprins in light brown) are highlighted in the red box. EDMD: Emery-Dreifuss Muscular Dystrophy, RD: Restrictive Dermopathy, HGPS: Hutchinson-Gilford Progeria Syndrome, MADA: Mandibuloacral Dysplasia type A, MADB: Mandibuloacral Dysplasia type B, DCM: Dilated Cardiomyopathy, DCM-CD: Dilated Cardiomyopathy with Conduction Defects, NGPS: Nestor-Guillermo Progeria Syndrome, ADLD: Autosomal Dominant Leukodystrophy, LGMD: Limb-Girdle Muscular Dystrophy, CMT: Charcot-Marie-Tooth, FPLD: Familial Partial Lipodystrophy, WRN: Werner’s Syndrome

Fig. 2

Prelamin A maturation process as a therapeutical target. Processing of prelamin A is a succession of enzymatic reactions that lead to a mature form of lamin A: The first step is the farnesylation of a cysteyl residue to obtain a farnesylated form of prelamin. Subsequently, a protease (ZMPSTE24 or RCE1) cleaves the aaX residues from the C-terminus tail. Finally, ZMPSTE24 protease cleaves the last 15 residues from the C-terminus to obtain mature prelamin A. In Hutchinson-Gilford Progeria Syndrome (HGPS) patient cells, the last cleavage by ZMPSTE24 does not take place leading to the abnormal accumulation of farnesylated lamin A. Potential therapeutic approaches are indicated in red: pravastatin, zoledronate, mono-aminopyrimidynes (mono-APs) and farnesyltransferase inhibitors (FTI)

Fig. 3

Predicted structure of ZMPSTE24 protease. ZMPSTE24 is a transmembrane protein located in the Outer Nuclear Membrane composed of seven hydrophobic domains (1 to 7, a catalytic domain (HELGH residues), and an endoplasmic reticulum retention motif (TMKQH residues)

Fig. 4

Summary of all known human diseases caused by mutations in genes coding for nuclear envelope components. The diversity of phenotypes induced by mutations in genes encoding nuclear envelope components, as well as the tissues affected by these, is illustrated and organized according to the localization of the mutated protein: (a) inner nuclear membrane, (b) nuclear lamina, and (c) outer nuclear membrane components. EDMD: Emery-Dreifuss Muscular Dystrophy, HGPS: Hutchinson-Gilford Progeria Syndrome, CMT: Charcot-Marie-Tooth Disease, ADLD: Autosomal Dominant Leukodystrophy