Genetics of Diseases of the Nuclear Envelope

Abstract

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.

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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.

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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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How to Cite close
Muchir, Antoine(Mar 2013) Genetics of Diseases of the Nuclear Envelope. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023858]