Genetics of Diseases of the Nuclear Envelope


Mutations in lamin A/C gene (LMNA) gene, which encodes A‐type nuclear lamins, cause a diverse range of diseases called laminopathies. These diseases selectively affect different tissues and organ systems. The main function of A‐type nuclear lamins is to provide structural scaffolding for the cell nucleus. However, the lamina also serves other functions, such as having a role in chromatin organisation, connecting the nucleus to the cytoplasm, gene transcription and mitosis. Since the first mutations in LMNA that causes a human disease identified in 1999, the A‐type lamins get a lot of focus from the scientific community. More than a decade later, promising therapeutic approaches emerge that will hopefully lead to new ways to treat or prevent laminopathies.

Key Concepts:

  • LMNA gene encodes ubiquitously expressed nuclear A‐type lamins.

  • LMNA mutations cause several diseases affecting specific tissues or progeroid syndrome, that is, laminopathies.

  • Studies on mouse models of LMNA‐dilated cardiomyopathy showed that MAP kinase and AKT/mTOR signalling are abnormally activated.

  • Post‐translational modifications of lamin A are important for the pathogenesis of progeria.

  • Small molecules have been successfully used in vivo to alleviate the symptoms of LMNA‐dilated cardiomyopathy and progeria.

Keywords: LMNA; A‐type lamins; dilated cardiomyopathy; Emery‐Dreifuss muscular dystrophy; familial partial lipodystrophy; progeria

Figure 1.

Diagram of molecular events linking LMNA mutations to diseases. LMNA gene – which encodes lamin A and lamin C by alternative splicing – can cause several diseases when mutated. These disorders can affect the striated muscle, the adipose tissue or the premature ageing. In the case of cardiac disease caused by LMNA mutation, it has been described an aberrant activation of MAPK and AKT/mTOR signalling. Pharmacological inhibition of these signalling improves the cardiac structure and function and ultimately the life span of mouse models of the disease. It has been described that abnormal post‐translational modification of pre‐lamin A leads to the production of progerin and causes HGPS. Pharmacological strategy targeting this phenomenon leads to a significant improvement of clinical symptoms in mice and human.



Arimura T, Helbling‐Leclerc A, Massart C et al. (2005) Mouse model carrying H222P‐Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies. Human Molecular Genetics 14(1): 155–169.

Ben Yaou R, Gueneau L, Demay L et al. (2006) Heart involvement in lamin A/C related diseases. Archives des Maladies du Coeur et des Vaisseaux 99(9): 848–855.

Bertrand AT, Renou L, Papadopoulous A et al. (2012) DelK32‐lamin A/C has abnormal location and induces incomplete tissue maturation and severe metabolic defects leading to premature death. Human Molecular Genetics 21(5): 1037–1048.

Bonne G, Di Barletta MR, Varnous S et al. (1999) Mutations in the gene encoding lamin A/C cause autosomal dominant Emery‐Dreifuss muscular dystrophy. Nature Genetics 21(3): 285–288.

Bonne G, Mercuri E, Muchir A et al. (2000) Clinical and molecular genetic spectrum of autosomal dominant Emery‐Dreifuss muscular dystrophy due to mutations of the lamin A/C gene. Annals of Neurology 48(2): 170–180.

Brodsky GL, Muntoni F, Miocic S et al. (2000) Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement. Circulation 101(5): 473–476.

Cao H and Hegele RA (2000) Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan‐type familial partial lipodystrophy. Human Molecular Genetics 9(1): 109–112.

Choi JC, Muchir A, Wu W et al. (2012) Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation. Science Translational Medicine 4(144): 144ra102.

Cohen AH and Sundeen JR (1976) The nuclear fibrous lamina in human cells: studies on its appearance and distribution. Anatomical Record 186(4): 471–476.

De Sandre‐Giovannoli A, Bernard R, Cau P et al. (2003) Lamin A truncation in Hutchinson–Gilford progeria. Science 300(5628): 2055.

Eriksson M, Brown WT, Gordon LB et al. (2003) Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 423(6937): 293–298.

Fatkin D, MacRae C, Sasaki T et al. (1999) Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction‐system disease. New England Journal of Medicine 341(23): 1715–1724.

Fawcett DW (1966) On the occurrence of a fibrous lamina on the inner aspect of the nuclear envelope in certain cells of vertebrates. American Journal of Anatomy 119(1): 129–145.

Fong L, Frost D, Meta M et al. (2006) A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Science 311(5767): 1621–1623.

Gerace L, Blum A and Blobel G (1978) Immunocytochemical localization of the major polypeptides of the nuclear pore complex‐lamina fraction. Interphase and mitotic distribution. Journal of Cell Biology 79(2 Pt 1): 546–566.

Gordon LB, Kleinmann ME, Miller DT et al. (2012) Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome. Proceedings of the National Academy of Sciences of the USA 109(41): 16666–16671.

Lin F and Worman HJ (1993) Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C. Journal of Biological Chemistry 268(22): 16321–16326.

Meune C, Van Berlo JH, Anselme F et al. (2006) Primary prevention of sudden death in patients with lamin A/C gene mutations. New England Journal of Medicine 354(2): 209–210.

Mounkes LC, Kozlov S, Hernandez L et al. (2003) A progeroid sydrome in mice is caused by defects in A‐type lamins. Nature 423(6937): 298–301.

Mounkes LC, Kozlov SV, Rottman JN et al. (2005) Expression of an LMNA‐N195 K variant of A‐type lamins results in cardiac conduction defects and death in mice. Human Molecular Genetics 14(15): 2167–2180.

Muchir A, Bonne G, van der Kooi AJ et al. (2000) Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Human Molecular Genetics 9(9): 1453–1459.

Muchir A, Pavlidis P, Decostre V et al. (2007) Activation of MAPK pathway links LMNA mutations to cardiomyopathy in Emery‐Dreifuss muscular dystrophy. Journal of Clinical Investigation 117(5): 1282–1293.

Muchir A and Worman HJ (2007) Emery‐Dreifuss muscular dystrophy. Current Neurology and Neuroscience Reports 7(1): 78–83.

Muchir A, Wu W, Choi JC et al. (2012) Abnormal p38a mitogen‐activated protein kinase signalling in dilated cardiomyopathy caused by lamin A/C gene mutation. Human Molecular Genetics 21(19): 4325–4333.

Sullivan T, Escalante‐Alcalde D, Bhatt H et al. (1999) Loss of A‐type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. Journal of Cell Biology 147(5): 913–920.

Wojtanik KM, Edgemon K, Viswanadha S et al. (2009) The role of LMNA in adipose: a novel mouse model of lipodystrophy based on the Dunnigan‐type familial poartial lipodystrophy mutation. Journal of Lipid Research 50(6): 1068–1079.

Worman HJ, Fong LG, Muchir A et al. (2009) Laminopathies and the long strange trip from basic cell biology to therapy. Journal of Clinical Investigation 119(7): 1825–1836.

Further Reading

Chen CY, Chi YH, Mutalif RA et al. (2012) Accumulation of the inner nuclear envelope protein Sun1 is pathogenic in progeric and dystrophic laminopathies. Cell 149(3): 565–577.

Nissan X, Blondel S, Navarro C et al. (2012) Unique preservation of neural cells in Hutchinson–Gilford progeria syndrome is due to the expression of the neural‐specific miR‐9 microRNA. Cell Reports 2(1): 1–9.

Osorio FG, Navarro CL, Cadinanos J et al. (2011) Splicing‐directed therapy in a new mouse model of human accelerated aging. Science Translational Medicine 3(106): 106ra107.

Ramos FJ, Chen SC, Garelick MG et al. (2012) Rapamycin reverses elevated mTORCs signalling in lamin A/C‐deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Science Translational Medicine 4(144): 144ra103.

Stewart CL, Kozlov S, Fong LG et al. (2007) Mouse models of the laminopathies. Experimental Cell Research 313(10): 2144–2156.

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Muchir, Antoine(Mar 2013) Genetics of Diseases of the Nuclear Envelope. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023858]