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Orphanet J Rare Dis. 2017 Aug 30;12(1):147. doi: 10.1186/s13023-017-0698-x.

Nuclear envelopathies: a complex LINC between nuclear envelope and pathology.

Janin A1,2,3,4, Bauer D1,2,3, Ratti F1,2,3, Millat G1,2,3,4, Méjat A5,6,7,8,9.

Author information

1
University Lyon, Université Claude Bernard Lyon 1, Institut NeuroMyoGène, F-69622, Villeurbanne, France.
2
CNRS UMR 5310, F-69622, Villeurbanne, France.
3
INSERM U1217, F-69622, Villeurbanne, France.
4
Laboratoire de Cardiogénétique Moléculaire, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Lyon, France.
5
University Lyon, Université Claude Bernard Lyon 1, Institut NeuroMyoGène, F-69622, Villeurbanne, France. alexandre.mejat@ens-lyon.fr.
6
CNRS UMR 5310, F-69622, Villeurbanne, France. alexandre.mejat@ens-lyon.fr.
7
INSERM U1217, F-69622, Villeurbanne, France. alexandre.mejat@ens-lyon.fr.
8
Nuclear Architecture Team, Institut NeuroMyoGène, CNRS UMR 5310 - INSERM U1217 - Université de Lyon - Université Claude Bernard Lyon 1, Lyon, France. alexandre.mejat@ens-lyon.fr.
9
Groupement Hospitalier Est - Centre de Biologie Est - Laboratoire de Cardiogénétique, 59 Boulevard Pinel, 69677, Bron, France. alexandre.mejat@ens-lyon.fr.

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

PMID:
28854936
PMCID:
PMC5577761
DOI:
10.1186/s13023-017-0698-x
[Indexed for MEDLINE]
Free PMC Article

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