Many human diseases are associated with NE protein defects 5. For example, a comprehensive proteomic study identified 13 known and 67 putative INM proteins, 23 of these proteins map to chromosome regions linked to a variety of dystrophies including congenital muscular dystrophy, Charcot-Marie-Tooth diseases and myotubular myopathy 6.

A great number of NE-associated diseases (Table 1) are directly or indirectly linked to inherited mutations in Lamin A (i.e. LMNA), a component of the nuclear lamina 7. Mutations in LMNA have been found in 11 clinically distinct tissue-specific degenerative diseases collectively termed "laminopathies", including muscular dystrophy, cardiomyopathy, lipodystrophy, and progeria (Table 1) 8. These laminopathies can be broadly divided into two groups: first, neuromuscular disorders affecting directly the skeletal muscle, cardiac muscle and peripheral nervous system [e.g. Emery-Dreifuss muscular dystrophy (EDMD), dilated cardiomyopathy (DCM), Limb-girdle muscular dystrophy 1B (LGMD1B)]; second, partial lipodystrophy syndromes with or without developmental abnormalities and premature aging [e.g. mandibuloacral dysplasia and Hutchison-Gilford Progeria Syndrome (HGPS)].

Of the laminopathies, HGPS is one of the more severe syndromes with affected individuals having a mean life span of approximately 13 years. More than 90% of HGPS are caused by a silent mutation (GGC>GGT; G608G) which leads to a mis-spliced form of Lamin A that is deleted for 50 amino acids at its C terminus. This mutated form of lamin A is termed "Progerin" 9. Patients expressing Progerin have aging-like features such as alopecia, sclerosis, wrinkling and arteriosclerosis at a prematurely early age 9.

Mutations in NE proteins Emerin or Lamin A/C may cause Emery-Dreifuss muscular dystrophy (EDMD; Table 1). EDMD is characterized by slowly progressive skeletal muscle wasting of the shoulder girdle and distal leg muscles, early contractures of the elbows and Achilles tendons, and cardiomyopathy with atrial ventricular block which eventually results in death 1011.

The Lamin B receptor (LBR), a member of the sterol reductase family, is evolutionarily conserved and integral to the inner nuclear membrane. LBR targets heterochromatin and lamin proteins to the nuclear membrane. Mutations in LBR cause the Pelger-Huët anomaly (PHA), an autosomal dominant disorder characterized by abnormal nuclear shape and chromatin disorganization in blood granulocytes (Table 1). Affected individuals show hypolobulated neutrophil nuclei with rough chromatin. Presumptively homozygous individuals have ovoid neutrophil nuclei, as well as varying degrees of developmental delay, epilepsy, and skeletal abnormalities 12.

Mouse models have been generated recently to investigate the biological relevance of different NE genes. Animals from most of these models exhibit developmental retardation and tissue-specific defects. Below, we enumerate the various mouse phenotypes that emerge from deficiencies in various NE components.

Most of the known INM proteins are associated with the nuclear lamina 19. Several mouse models have been established to investigate the physiological consequences of a loss of interaction between the nuclear lamina and the INM proteins.

In addition to significant changes in the nuclear shape, the Hutchinson-Gilford progeria syndrome (HGPS) is associated with prominent clustering of nuclear pores 32. While the link between spatial distribution of nuclear pores and a premature aging phenotype remains to be elucidated, recent findings in mouse models suggest that NPCs have additional functions in chromatin organization, gene regulation and cell cycle progression which are independent of the roles they play in nuclear transport 33. Below, we survey mouse data on the involvement of the nuclear pore proteins in protecting chromosomal integrity.

The eukaryotic genome is tightly compacted to fit into the confines of the nucleus. Accumulating evidence agree that the three-dimensional distribution of the chromosomes in the nucleus is nonrandom and falls into "territories" 4647. Thus, the transcriptional state of genes may be dictated by how they are positioned and distributed in different nuclear space 48. Based on electron microscopic findings, the nuclear periphery was initially thought to be occupied by transcriptionally silent heterochromatin. Recent evidence, however, suggests that the association of chromatin with the NE can result in gene activation 49. Thus, in yeast, transcriptional activation correlates with chromatin association to NPCs, and the activation of certain genes often results in their dynamic relocation to the nuclear periphery 495051. In some respects, it is biologically parsimonious that gene transcription occurs at the nuclear periphery because the synthesized mRNA can then be readily exported through the nuclear pores. On the other hand, genome-wide analysis in Drosophila cells has also revealed clusters of transcriptionally silent and hypo-acetylated genes that interact with Lamin B1 and are positioned at the nuclear periphery 52. Using three-dimensional DNA-immuno-FISH, Reddy et al. demonstrated that an Emerin, Lamin A, Lamin B and LAP2 complex can result in establishing a distinctively repressive chromatin structure that silences transcription 53. Within this complex, proteins like LAP2 recruits histone deacetylases like HDAC3, causing deacetylation of histone H4 leading to transcriptional repression 54. In distinction with LAP2, the human SUN-domain protein 1 appears to recruit a histone acetyltransferase that acts to regulate chromatin decondensation 20. Collectively, the findings suggest that NE and NE-associated proteins can recruit chromatin and regulatory factors that either activate or inactivate gene transcription. In instances of aberrant loss of heterochromatin regulation, this finding is often pathologically associated with prematurely aging HGPS cells 55.

Individuals with progeroid syndromes show accelerated aging. Molecularly, aging is a process characterized by the accumulation of somatic damages and the progressive failure in the homeostasis of gene maintenance - repair whose imbalance can trigger apoptosis and senescence (Fig. 2) 5657. A-type lamins are necessary for normal DNA strand rejoining after exposure to irradiation 58. Thus, HGPS fibroblasts have delayed DNA-damage checkpoint response and defective DNA repair (Fig. 2), suggesting that genomic instability may contribute to laminopathy-based premature aging 59. Indeed, in addition to delayed DNA repair responses, telomeres in fibroblasts from HGPS patients are shorter than in age-matched controls suggesting that altered telomere dynamics and/or structure may be an additional underlying component of progeroid disease (Fig. 2) 5860.

In higher eukaryotic cells when the NE breaks down, the nuclear lamina depolymerizes into both soluble and membrane-associate pools (Fig. 3). NPC subunits are either translocated to kinetochores or dispersed into the cytoplasm, while the nuclear membrane and INM proteins merge into the ER network. During the anaphase/telophase transition, the NE components reassemble around the condensed chromatin (Fig. 3).

At the conclusion of mitosis as the NE reforms, the NE protein complex associates with discrete regions of mitotic chromatin in a sequential manner (Fig. 3). LAP2 and a subfraction of BAF form defined complexes in chromatin core regions 2061. SUN1 and a subset of nucleoporins wrap the lateral margins of newly separated sister chromatids (Fig. 3). The nuclear lamina and Emerin then coalesce with SUN1 and LAP2 in telophase 20. Thus, chromatin-interacting membrane proteins such as LBR, MAN1, LAP2, and the trans-membrane nucleoporins Ndc1 and POM121 collaborate to rapidly reestablish the nuclear compartment at the end of mitosis and facilitate NE reformation 62. In the newly reformed nucleus, the SUN1 protein recruits a membrane associated histone acetyltransferase hALP to acetylate histones to decondense the DNA, thereby preparing the cell for transcription during the next interphase 20. The complexity of these events underscores the importance of nuclear envelope physiology to the normal life cycle of the cell and explains why envelope defects lead to significant diseases.

Here, we review in brief the pleiotropic functions of NE and NE-associated proteins in normal and pathological physiology. Based on extant data, it is clear that defects in NE-associated proteins can manifest as devastating diseases such as the progeroid syndromes. What is less clear is whether the syndromes occur due to a loss of a normal function (i.e. Lamin A mutation) or a gain of an abnormal dominant negative activity (i.e. expression of a mutant Progerin protein) or both. Going forward, the study of envelopathies and laminopathies may reveal balanced contributions from both losses and gains in functions to disease development. While NE proteins were originally thought to serve only simple structural roles, much more remain to be discovered about these factors for their complex regulatory functions.