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How do mutations in lamins A and C cause disease?
Howard J. Worman1 and Jean-Claude Courvalin2
1Department of Medicine and Department of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York, USA2Département de Biologie Cellulaire, Institut Jacques Monod, Université Paris 7, Paris, France
Address correspondence to: Howard J. Worman, Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, Box 83, New York, New York 10032, USA. Phone: (212) 305-8156; Fax: (212) 305-6443; E-mail: hjw14@columbia.edu.
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1Department of Medicine and Department of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York, USA2Département de Biologie Cellulaire, Institut Jacques Monod, Université Paris 7, Paris, France
Address correspondence to: Howard J. Worman, Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, Box 83, New York, New York 10032, USA. Phone: (212) 305-8156; Fax: (212) 305-6443; E-mail: hjw14@columbia.edu.
Find articles by Courvalin, J. in: PubMed | Google Scholar
Published February 1, 2004 - More info
J Clin Invest. 2004;113(3):349–351. https://doi.org/10.1172/JCI20832.
© 2004 The American Society for Clinical Investigation
The nuclear lamina is a meshwork of intermediate filaments, primarily localized on the inner aspect of the inner nuclear membrane, that forms from polymerization of proteins called lamins (1–3). In humans, two genes encode B-type lamins, which are constitutively expressed in somatic cells. LMNA (Lmna in mice) encodes developmentally regulated A-type lamins, including the major somatic cell isoforms lamins A and C (4).
Since 1999, mutations in LMNA have been shown to cause several different inherited diseases (Table 1). Some, such as Emery-Dreifuss muscular dystrophy (EDMD) and Dunnigan-type familial partial lipodystrophy (FPLD), are rather tissue-specific (5). Others, such as Hutchinson-Gilford progeria syndrome, which is caused by a unique mutation in lamin A (6, 7), are more generalized. Before these discoveries, the predominant functions of lamins A and C were thought to be to provide mechanical support to the nucleus and to anchor “silent” heterochromatin to the inner nuclear membrane. The discoveries linking lamins A and C to inherited disorders have led to a new question: How do mutations in these proteins, expressed in nearly all differentiated somatic cells, cause different diseases, some of which are tissue-specific?
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Impaired nuclear mechanics leading to alterations in gene expression
Nikolova et al. (14) carefully analyzed lamin A/C–deficient mice and showed that they develop dilated cardiomyopathy with an impairment of physiological hypertrophy. They showed that nuclei of cardiac tissue and isolated myocytes have abnormal nuclear architecture with fragmented centromeric heterochromatin relocated from the periphery to the interior of the nucleus, and they correlated these alterations with possible defects in nucleocytoplasmic transport and gene expression. They also observed changes in desmin localization and speculated that a cellular skeleton integrating cytoplasmic desmin and nuclear lamina networks at the nuclear pore complexes is altered (Figure 1). Although there is no evidence for connections between the lamina and desmin networks in vivo, the strength of this study is the demonstration of impressive changes in chromatin structure, which may indeed have pathological consequences. In general, there is a correlation between gene activity and nuclear location with genes physically localized near the periphery of the nucleus being inactive (16). Dynamic changes in gene activation may also occur during cellular differentiation, with silenced genes preferentially shifted to the nuclear periphery, close to centromeric heterochromatin, and activated ones translocated to a more central, euchromatic environment (17). A similar chromatin-reorganizing mechanism may normally be operative in nuclei of differentiating myoblasts or as a protective response in differentiated myocytes; loss of lamins A and C may disrupt this, leading to inappropriate gene activation or repression and resultant myopathy.
Figure 1Schematic diagrams showing nuclear envelopes of a normal myocyte (a) and a myocyte from a mouse lacking lamins A and C (b). The nuclear envelope contains the inner nuclear membrane, pore membranes, and the outer nuclear membrane, which is directly continuous with the endoplasmic reticulum (ER). It also contains the nuclear lamina and nuclear pore complexes. The nuclear lamina of a normal myocyte (a) is composed of A-type (lamins A and C) and B-type (lamin B) lamins, which form a meshwork of intermediate filaments (yellow, red, and green). At the periphery of the nucleus, heterochromatin is preferentially associated with the inner nuclear membrane and the lamina. Putative connections (? in figure) may exist between cytoplasmic desmin filaments and the external faces of the nuclear pore complexes. In a myocyte of a lamin A/C–deficient mouse (b), the lamina is composed of only B-type lamins (green), and the nuclear envelopes are irregularly shaped with morphological abnormalities. Nikolova et al. (14) showed that heterochromatin is largely relocated from the nuclear envelope to the interior, which could cause alterations in gene expression. They also showed changes in desmin localization and hypothesized that this may result from alterations of its putative association (? in figure) with the nuclear envelope. Using fibroblasts from lamin A/C–deficient mice, Lammerding et al. (15) showed that nuclear deformities are increased by applied mechanical strain with resultant defective mechanotransduction and attenuated expression of mechanoresponsive genes. Adapted with permission from the Massachusetts Medical Society, Copyright 2000 (20). All rights reserved.
Lammerding et al. (15) directly explored nuclear mechanics and mechanotransduction in cultured embryonic fibroblasts from lamin A/C–deficient mice. Although connective tissue is not obviously abnormal in these mice, fibroblasts have misshaped nuclei with ultrastructural damage, validating the use of this cell type. Using magnetic-bead microrheology, the authors showed that the cytoplasm and nucleus have decreased stiffness in lamin A/C–deficient fibroblasts. They further showed that, in response to applied mechanical strain, these fibroblasts have increased nuclear deformations (Figure 1), defective mechanotransduction, attenuated expression of mechanosensitive genes activated by NF-κB, and diminished viability. Cytokine-stimulated NF-κB transcriptional activation was also attenuated.
These two studies (14, 15) suggest that impaired nuclear mechanics and secondary alterations in gene expression may cause striated muscle damage in subjects with certain lamin A/C mutations. By preferentially affecting transcriptional responses to mechanical stress or possibly other signals in nonmuscle cells, different mutations in lamins A and C may generate a diversity of tissue-specific pathological phenotypes. More generalized phenotypes, such as premature-aging syndromes, may result from mutations that cause more global abnormalities in chromatin structure and transcriptional control, much as classical Werner syndrome may result from mutations in a DNA helicase (18). Since the puzzling variety of diseases caused by mutations in lamins A and C has generated such a flurry of speculations as to pathogenic mechanisms (including our own work), it is refreshing to see solid experimental data that address this matter in this issue of the JCI.
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