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Physiology 19: 309-314, 2004; doi:10.1152/physiol.00022.2004
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Physiology, Vol. 19, No. 5, 309-314, October 2004
© 2004 Int. Union Physiol. Sci./Am. Physiol. Soc.

REVIEW

The Nuclear Envelope and Human Disease

Antoine Muchir and Howard J. Worman

Departments of Medicine and of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York 10032

hjw14{at}columbia.edu


   Abstract
 
Mutations in nuclear lamins A and C, intermediate filament proteins of the nuclear envelope, cause diseases affecting various tissues and the aging process. We review what is known about nuclear lamin function and the different diseases caused by mutations in lamins A and C and associated inner nuclear membrane proteins.


   Introduction
Top
 Introduction
Nuclear Envelope and Nuclear...
 Inner Nuclear Membrane Proteins...
 Lamins are Likely Involved...
 Mutations in Lamins A/C...
 How do Mutations in...
 References
 
A relatively recent revolution occurred in the field of muscle pathophysiology when mutations in nuclear envelope proteins were shown to cause muscular dystrophy and cardiomyopathy (3, 4). This set the stage for analyzing other hereditary diseases, and, over the next few years, mutations in nuclear lamins A and C were shown to cause diseases specifically affecting several different tissues. These discoveries are changing our view of the nuclear envelope, an organelle previously thought to have primarily the same structural role in all cells.


   Nuclear Envelope and Nuclear Lamina
Top
 Introduction
 Nuclear Envelope and Nuclear...
Inner Nuclear Membrane Proteins...
 Lamins are Likely Involved...
 Mutations in Lamins A/C...
 How do Mutations in...
 References
 
In higher eukaryotic cells, the nucleus is surrounded by an envelope composed of three parts: the nuclear membranes (inner, outer, and pore), the nuclear pore complexes, and the nuclear lamina (FIGURE 1Go). The outer nuclear membrane is continuous with the rough endoplasmic reticulum, whereas lamina is linked to the inner nuclear membrane by integral proteins. The lamina is a fibrous meshwork composed of intermediate filament proteins called lamins (types A and B) (18, 27). Lamins contain {alpha}-helical rod domains flanked by globular amino-terminal head and carboxy-terminal tail domains. They form coiled-coiled dimers that polymerize to form filaments.



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  		FIGURE 1. Schematic diagram of the nuclear envelope showing the nuclear membranes, nuclear lamina, and pore complexes
Selected integral proteins of the inner nuclear membrane and their topologies are also shown. LBR, lamin B receptor; LAP, lamina-associated polypeptide.

 
A-type lamins, which arise by alternative splicing of RNA encoded by the same gene, LMNA (24), are widely expressed in differentiated cells but are lacking from early embryos and some undifferentiated cells. Human lamins A and C are identical for their first 566 amino acids but are distinct at their carboxy-terminal ends. Lamin C has six unique carboxy-terminal amino acids, and prelamin A has 98 unique carboxy-terminal amino acids. Prelamin A is farnesylated on the cysteine of a carboxy-terminal CAAX box and is then endoproteolytically processed to yield mature lamin A, which lacks the last 18 amino acids (44). A metalloproteinase (Zmpste24/Face-1) is involved in this posttranslational process (23). The mammalian somatic cell B-type lamins are lamin B1 and lamin B2, which are transcribed from the LMNB1 and LMNB2 genes, respectively. B-type lamins are present in all somatic cells and are coexpressed with A-type lamins in differentiated cells. B-type lamins are permanently farnesylated at carboxy-terminal cysteines.


   Inner Nuclear Membrane Proteins Associated with Lamins
Top
 Introduction
 Nuclear Envelope and Nuclear...
 Inner Nuclear Membrane Proteins...
Lamins are Likely Involved...
 Mutations in Lamins A/C...
 How do Mutations in...
 References
 
The lamina interacts with integral proteins of the inner nuclear membrane. A recent proteomics analysis suggests that as many as eighty transmembrane proteins are localized to the inner nuclear membrane in interphase cells (40). Only a few of these proteins have been characterized in detail. Mutations in two of them have so far been shown to cause human diseases.

Emerin is composed of 254 amino acids in humans and has a 220-amino acid nucleoplasmic amino-terminal domain, a single transmembrane segment, and a short luminal tail (FIGURE 2Go). The nucleoplasmic domain of emerin binds to lamins A and C and to chromatin-associated proteins such as barrier-to-autointegration factor (8, 39, 42, 47). Except for these protein-protein interactions, the functions of emerin remain unknown. As discussed below, mutations in emerin cause X-linked Emery-Dreifuss muscular dystrophy (3).



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  		FIGURE 2. Schematic diagram of emerin and LBR proteins
A: emerin is a transmembrane protein of the inner nuclear membrane that interacts with lamin A/C, actin, a transcription factor [germ cell-less (GCL)], and a splice factor (YT521-B). Emerin contains a LEM domain at its amino terminus. B: LBR is an inner nuclear membrane protein consisting of a nucleoplasmic amino-terminal domain, 8 transmembrane segments, and a short carboxy-terminal tail. LBR interacts with B-type lamins, with heterochromatin protein 1 (HP1), and with DNA.

 
Human lamin B receptor (LBR) is a 615-amino acid protein composed of a nucleoplasmic amino-terminal domain of ~210 amino acids followed by a mostly hydrophobic domain with eight putative transmembrane segments (53). LBR interacts with B-type lamins (51, 53), orthologs of Drosophila heterochromatin protein 1 (52), and DNA (53) (FIGURE 2Go). The hydrophobic domain of LBR has high sequence similarity to sterol reductases in yeast, plants, and mammals (20, 41). In 2002, Hoffmann et al. showed that mutations in LBR cause Pelger-Huët anomaly, a rare autosomal dominantly inherited condition characterized by incomplete segmentation of granulocyte nuclei (19). Homozygous mutations in LBR have been reported in a case of HEM/Greenberg skeletal dysplasia (50). This is an autosomal recessive chondrodystrophy with growth retardation, epilepsy, skeletal abnormalities, and a deficiency of 3 ß-hydroxysterol {Delta} 14-reductase deficiency.


   Lamins are Likely Involved in Several Cellular Processes
Top
 Introduction
 Nuclear Envelope and Nuclear...
 Inner Nuclear Membrane Proteins...
 Lamins are Likely Involved...
Mutations in Lamins A/C...
 How do Mutations in...
 References
 
To obtain insights into the physiological functions of lamins A and C, Stewart and collaborators (47) generated a knockout murine model. Homozygous knockout mice deficient in lamins A and C have normal early development, but within the first 4 wk of life they develop regional muscular dystrophy and cardiomyopathy. Hence, lamins A and C are not essential for survival of differentiated cells.

One likely function of the nuclear lamina is maintaining nuclear shape. Lack of the only lamin in nematode (25), lack of lamins A and C in human and mouse fibroblasts (33, 47), and point mutations in human lamins A and C (32, 49) induce changes in nuclear shape with herniations of the nuclear envelope. Lamins also appear to function in DNA replication and transcription. When "headless" lamin mutants are expressed in culture cells, the lamina structure is disrupted, inducing impairment of DNA synthesis (29, 46) and inhibition of RNA polymerase II activity (45). Several investigators have hypothesized that lamins may regulate tissue-specific or stress-induced gene expression. Along these lines, Favreau et al. (17) showed that expression of a mutant lamin A that causes Emery-Dreifuss muscular dystrophy inhibited the in vitro differentiation of C2C12 myoblasts and that this correlated with low levels of expression of myogenin and persistence of hyperphosphorylated retinoblastoma protein. Lammerding et al. (22) showed that transcription from genes normally activated by mechanical stress is attenuated in stretched fibroblasts from lamin A/C-deficient mice.


   Mutations in Lamins A/C and Human Diseases
Top
 Introduction
 Nuclear Envelope and Nuclear...
 Inner Nuclear Membrane Proteins...
 Lamins are Likely Involved...
 Mutations in Lamins A/C...
How do Mutations in...
 References
 
During the past five years, mutations in lamins A and C have been shown to cause a wide range of human disorders. These disorders primarily affect striated muscle, adipose tissue, or peripheral nerves. Other mutations cause syndromes with features of premature aging.

Striated muscle diseases
Emery-Dreifuss muscular dystrophy, described for the first time in 1961 (12), is a heterogeneous condition with X-linked and autosomal inheritance. It is typically characterized by a triad of symptoms: 1) early contractures of Achilles’ tendons, elbows, and paraspinous cervical muscles, 2) slow progressive muscle wasting and weakness with a humeroperoneal distribution, and 3) dilated cardiomyopathy with early atrioventricular block and subsequent ventricular dysrhythmia (14). In 1994, Bione et al. (3) used positional cloning to show that mutations in emerin were responsible for X-linked Emery-Dreifuss muscular dystrophy. Subsequently, emerin was localized to the inner nuclear membrane (26, 34). In 1999, Bonne et al. (4) identified mutations in lamins A and C in families with autosomal dominant Emery-Dreifuss mus-cular dystrophy.

Limb-girdle muscular dystrophies represent a genetically heterogeneous group of disorders with a limb girdle distribution of affected muscles. In 1997, Van der Kooi et al. (48) mapped the gene for the then newly described autosomal dominant limb girdle muscular dystrophy type 1B to chromosome 1q11-21. Subjects with this condition have a cardiac abnormality similar to that in Emery-Dreifuss muscular dystrophy. Given the chromosomal localization of the disease locus, Muchir et al. (31) considered LMNA to be a candidate gene and showed that it was mutated in three affected families. Subjects with dilated cardiomyopathy with conduction defect, an autosomal dominant disorder, also have a similar cardiac abnormality to Emery-Dreifuss and limb-girdle type 1B muscular dystrophies. In 1999, Fatkin et al. (16) showed that LMNA was mutated in several cases of dilated cardiomyopathy with conduction defect.

The three striated muscle diseases caused by mutations in lamins A and C are likely to be the same disorder: a primary cardiomyopathy with variable skeletal muscle involvement. There is no clear correlation between the clinical phenotype and type or localization of the mutations in proteins, which are generally amino acid substitutions or short deletions throughout the sequences. In two members of one family, the same mutation resulted in a clinical diagnosis of Emery-Dreifuss muscular dystrophy and limb girdle muscular dystrophy (5). Genetic heterogeneity of skeletal muscle involvement has also been reported in five different cases with the same amino acid substitution (28). Further studies are needed to identify genetic and environmental factors that may modify phenotypes among subjects harboring mutations in lamins A and C that cause striated muscle disease.

Lipodystrophy syndromes
Lipodystrophies are a heterogeneous group of diseases with partial or generalized loss of adipose tissue usually associated with insulin resistance and diabetes mellitus. Dunnigan-type partial lipodystrophy is an autosomal dominant condition characterized by loss of adipose from the extremities, excess adiposity of the face and neck, and insulin resistance starting at puberty (13). In 2000, two groups first identified mutations in LMNA in subjects with this disorder (6, 43). The majority are missense mutations in exon 8, changing arginine 482 in lamins A and C to a tryptophan, glutamine, or leucine. These mutations do not overlap with the mutations that cause the other diseases. The most commonly mutated amino acids are located on a solvent-exposed surface of an immunoglobulin-like fold, suggesting that this part of lamin A/C interacts with proteins with adipose-selective functions (11, 21).

Mandibuloacral dysplasia is an autosomal recessive disorder characterized by mandibular and clavicular hypoplasia, acro-osteolysis, delayed closure of the cranial suture, joint contractures, and partial lipodystrophy (54). In 2002, Novelli et al. (35) identified a missense mutation at amino acid 527 in lamins A and C in five families affected by this disease, suggesting a founder effect. Knockout mice deficient in the Zmpste24 metalloproteinase and human subjects carrying mutations in the ortholog both develop features of mandibuloacral dysplasia (1, 2, 37). Hence defective processing of prelamin A may cause this condition.

Peripheral neuropathy
Charcot-Marie-Tooth disorders are a group of hereditary motor and sensory neuropathies with muscle wasting, foot deformities, and axonal degeneration. A rare autosomal recessive variant, type 2B1, is caused by a specific mutation that changes an arginine to a cysteine at amino acid 298 of lamins A and C (10). LMNA knockout mice also have a reduction in axon density and demyelinated axons (10).

Premature aging syndromes
Progeroid syndromes are dramatic disorders characterized by premature aging. Hutchinson-Gilford progeria syndrome is a rare autosomal dominant condition characterized by growth retardation, facial hypoplasia, loss of subcutaneous adipose tissue, and premature atherosclerosis leading to death usually by thirteen years of age. In 2003, a de novo single-base substitution, GGC > GGT at codon 608 within exon 11 of LMNA, was identified in subjects with Hutchinson-Gilford progeria (9, 15). Eriksson et al. (15) identified this mutation in 18 of 20 subjects with classical Hutchinson-Gilford progeria syndrome and a GGC > AGC mutation at the same codon in one other. These mutations create RNA splice donor sites, leading to the expression of a truncated prelamin A lacking 50 amino acids from its carboxy-terminal tail (15). Homozygous knock-in mice carrying a mutation predicted to change an arginine to a proline at amino acid 530 in lamin A/C, but actually causing abnormal RNA splicing in mice, also have a progeria phenotype (30). In contrast to RNA splicing mutations, missense mutations in LMNA predicted to cause amino acid substitutions have been described in subjects with a diagnosis of atypical Werner syndrome, another progeria (7), and in one subject studied by Eriksson et al. (15) with a diagnosis of Hutchinson-Gilford progeria but atypical clinical features.


   How do Mutations in Inner Nuclear Membrane Proteins Cause Human Disease?
Top
 Introduction
 Nuclear Envelope and Nuclear...
 Inner Nuclear Membrane Proteins...
 Lamins are Likely Involved...
 Mutations in Lamins A/C...
 How do Mutations in...
References
 
The pathophysiological mechanisms of how mutations in these proteins cause different diseases remain unknown. Investigators in the field have proposed two general hypotheses. The "mechanical stress" hypothesis proposes that abnormalities in nuclear structure lead to increased susceptibility to cellular damage by physical strain. It is attractive to explain disorders of striated muscle, but the only experimental evidence so far comes from observations on cultured cells. Transfected cells expressing mutant A-type lamins and fibroblasts from patients with lamin A/C mutations often have abnormalities in nuclear morphology (15, 32, 36, 38, 49). Fibroblasts from subjects with Dunnigan-type partial lipodystrophy are also susceptible to damage by heat shock (49) and the cytoplasm and nucleus of fibroblasts from LMNA knockout mice have decreased stiffness (22). The "gene expression" hypothesis proposes that interaction between the nuclear envelope and chromatin regulates tissue-specific gene expression and that mutations in lamins and associated proteins alter this. This hypothesis is based primarily on effects of lamins on transcription and interactions between nuclear envelope and chromatin components. These hypotheses form the basis for future experimental studies addressing how lamins and other nuclear envelope proteins lead to pathophysiological alterations in different tissues.


   Acknowledgments
 
Our work on the nuclear envelope has been supported by the National Institutes of Health (AR-48997 and DK-62351), the Muscular Dystrophy Association, the American Diabetes Association, the Human Frontiers Science Program, and Fundation Recherche Médicale.


   References
Top
 Introduction
 Nuclear Envelope and Nuclear...
 Inner Nuclear Membrane Proteins...
 Lamins are Likely Involved...
 Mutations in Lamins A/C...
 How do Mutations in...
 References
 

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