Life at the edge: the nuclear envelope and human disease

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Abstract
The nuclear envelope forms a selective barrier between the nucleus and cytoplasm. It features inner and outer nuclear membranes (INM and ONM, respectively), which are spanned by nuclear pore complexes. A protein meshwork – the nuclear lamina – lines the nuclear face of the INM. The INM contains unique membrane proteins, most of which interact with underlying chromatin and/or components of the nuclear lamina. INM proteins include emerin, as well as lamina associated protein (LAP)1 and LAP2 family members. The main components of the nuclear lamina are intermediate filament proteins known as A- and B-type lamins. Lamins interact with both INM proteins and chromatin. Whereas B-type lamins are expressed in all cell types, A-type lamins are absent from early embryonic cells. Defects in genes that encode nuclear lamina and lamina-associated proteins give rise to a group of human hereditary diseases known as laminopathies. Emerin and lamin A mutations are associated with X-linked and autosomal forms of Emery–Dreifuss muscular dystrophy, respectively. Other lamin A mutations give rise to disorders that include Dunnigan type familial partial lipodystrophy and type 2 Charcot-Marie-Tooth disease. The disease mechanisms that are associated with lamin A mutations are not yet clear. It is possible that certain disorders, in particular cardiac and skeletal myopathies might result from nuclear structural defects that might be manifested in increased nuclear fragility. However, no single mechanism can account for all of the laminopathies .