Cellular Basis of Laminopathies

Abstract

The nuclear lamina is the main architectural component of a eukaryotic nucleus. More than an inert scaffold, the lamina is essential for maintaining proper nuclear organisation, epigenetic composition, transcriptional regulation and cell cycle progression. Mutations within lamin genes lead to a wide range of diseases known as laminopathies, among which the striking premature aging disease Hutchinson–Gilford progeria syndrome (HGPS) is the most well known. Studies regarding the cellular basis of laminopathies have advanced our knowledge of the nuclear lamina and yielded remarkable insights into the process of normal human aging. Understanding the molecular mechanisms responsible for disease manifestations has also led to the development of novel therapeutic strategies to address lamina‐related diseases. Ultimately, scientists and clinicians seek to provide treatment options to laminopathy patients to alleviate symptoms and perhaps to cure these diseases in the future.

Key Concepts:

  • Mutations in genes encoding lamin proteins lead to a wide range of diseases known as laminopathies.

  • The nuclear lamina plays essential roles in maintaining nuclear architecture, chromatin organisation, cellular differentiation and gene expression.

  • Studies of the molecular mechanisms underlying laminopathies have led to advances in the understanding of lamin structure and function.

  • Progerin, the mutant form of lamin A expressed in Hutchinson–Gilford progeria syndrome, is also present in normal individuals, albeit at a low level.

  • Recent advances have led to the development of noval therapeutic options for patients suffering from HGPS.

Keywords: nuclear lamina; lamins; laminopathies; muscular dystrophy; Hutchison–Gilford progeria syndrome; epigenetics; farnesylation; morpholino

Figure 1.

Lamin processing. Blue and black lines indicate different amino acid sequences.

close

References

Anisimov VN, Zabezhinski MA, Popovich IG et al. (2010) Rapamycin extends maximal lifespan in cancer‐prone mice. American Journal of Pathology 176(5): 2092–2097.

Bione S, Maestrini E, Rivella S et al. (1994) Identification of a novel X‐linked gene responsible for Emery‐Dreifuss muscular dystrophy. Nature Genetics 8(4): 323–327.

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

Bruston F, Delbarre E, Ostlund C et al. (2010) Loss of a DNA binding site within the tail of prelamin A contributes to altered heterochromatin anchorage by progerin. FEBS Letters 584: 2999–3004.

Cao K, Capell BC, Erdos MR, Djabali K and Collins FS (2007) A lamin A protein isoforms overexpressed in Hutchinson‐Gilford progeria syndrome interferes with mitosis in progeria and normal cells. Proceedings of the National Academy of Sciences of the USA 104(12): 4949–4954.

Cao K, Graziotto JJ, Blair CD et al. (2011a) Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson‐Gilford progeria cells. Science Translational Medicine 3(89): 89ra58.

Cao K, Blair CD, Faddah DA et al. (2011b) Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts. Journal of Clinical Investigation 121(7): 2833–2844.

Capanni C, Cenni V, Mattioli E et al. (2003) Failure of lamin A/C to functionally assemble in R482L mutated familial partial lipodystrophy fibroblasts: altered intermolecular interaction with emerin and implications for gene transcription. Experimental Cell Research 291(1): 122–134.

Capell BC and Collins FS (2006) Human laminopathies: nuclei gone genetically awry. Nature Genetics 7: 940–952.

Capell BC, Erdos MR, Madigan JP et al. (2005) Inhibiting Farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson‐Gilford progeria syndrome. Proceedings of the National Academy of Sciences of the USA 102: 12879–12884.

Capell BC, Olive M, Erdos MR et al. (2008) A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model. Proceedings of the National Academy of Sciences of the USA 105(41): 15902–15907.

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

De Sandre‐Giovannoli A, Chaouch M, Kozlov S et al. (2002) Homozygous defects in LMNA, encoding lamin A/C nuclear‐envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot‐Marie‐Tooth disorder type 2) and mouse. American Journal of Human Genetics 70(3): 726–736.

Dechat T, Shimi T, Adam SA et al. (2007) Alterations in mitosis and cell cycle progression caused by mutant lamin A known to accelerate human aging. Proceedings of the National Academy of Sciences of the USA 104: 4955–4960.

Dechat T, Adam SA, Taimen P et al. (2010) Nuclear Lamins. Cold Spring Harbor Perspectives in Biology 2(11): a000547.

Dechat T, Pfleghaar K, Sengupta K et al. (2008) Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin. Genes & Development 22(7): 832–853.

Delbarre E, Tramier M and Coppey‐Moisan M (2006) The truncated prelamin A in Hutchinson‐Gilford progeria syndrome alters segregation of A‐type and B‐type lamin homopolymers. Human Molecular Genetics 15: 1113–1122.

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

Filesi I, Gullotta F and Lattanzi G (2005) Alterations in nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy. Physiological Genomics 23: 150–158.

Folker ES, Ostlund C, Luxton GW, Worman HJ and Gundersen GG (2011) Lamin A variants that cause striated muscle disease are defective in anchoring transmembrane actin‐associated nuclear lines for nuclear movement. Proceedings of the National Academy of Sciences of the USA 108(1): 131–136.

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

Fong LG, Ng JK, Meta M et al. (2004) Heterozygosity for LMNA deficiency eliminates the progeria‐like phenotypes in Zmpste24‐deficient mice. Proceedings of the National Academy of Sciences of the USA 101(52): 18111–18116

Glynn MW and Glover TW (2005) Incomplete processing of mutant lamin A in Hutchinson‐Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Human Molecular Genetics 14: 2959–2969.

Goldman AE, Maul G, Steinert PM, Yang HY and Goldman RD (1986) Keratin‐like proteins that coisolate with intermediate filaments of BHK‐21 cells are nuclear lamins. Proceedings of the National Academy of Sciences of the USA 83: 3839–3843.

Goldman RD, Shumaker DK and Erdos MR (2004) Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson‐Gilford progeria syndrome. Proceedings of the National Academy of Sciences of the USA 101: 8963–8968.

Goldman RD, Gruendbaum Y, Moir RD, Shumaker DK and Spann TP (2002) Nuclear lamins: building blocks of nuclear architecture. Genes & Development 16: 533–547.

Johnson BR, Nitta RT and Frock RL (2004) A‐type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteosomal degradation. Proceedings of the National Academy of Sciences of the USA 101: 19677–19682.

Kubben N, Voncken JW and Demmers J (2011) Identification of differential protein interactors of lamin A and progerin. Nucleus 1(6): 513–525.

Liu G, Barkho BZ, Ruiz S et al. (2011) Recapitulation of premature ageing with iPSCs from Hutchinson‐Gilford progeria syndrome. Nature 472: 221–225.

Loewinger L and McKeon F (1998) Mutations in the nuclear lamina proteins result in their aberrant assembly in the cytoplasm. EMBO Journal 7: 2301–2309.

Lombardi F, Fasciglione GF and D'Apice MR (2008) Increased release and activity of matrix metalloproteinase‐9 in patients with mandibuloacral dysplasia type A, a rare premature ageing syndrome. Clinical Genetics 74(4): 374–383.

Lombardi F, Gullotta F and Columbaro M (2007) Compound heterozygos ity for mutations in LMNA in a patient with a myopathic and lipodystrophic mandibuloacral dysplasia type A phenotype. Journal of Clinical Endocrinology and Metabolism 92(11): 4467–4471.

Marji J, O'Donoghue SI and McClintock D (2010) Defective Lamin A‐Rb signaling in Hutchinson‐Gilford progeria syndrome and reversal by farnesyltransferase inhibition. PLoS ONE 5(6): e11132.

Musich PR and Zou Z (2009) Genomic instability and DNA damage responses in progeria aging from defective maturation of prelamin A. Aging 1: 28–37.

Novelli G, Muchir A and Sangiuolo F (2002) Mandibuloacral dysplasia is caused by a mutation in LMNA‐encoding lamin A/C. American Journal of Human Genetics 71: 426–431.

Olive M, Harten I and Mitchell R (2010) Cardiovascular pathology in Hutchinson‐Gilford progeria: correlation with the vascular pathology of aging. Arteriosclerosis, Thrombosis, and Vascular Biology 30(11): 2301–2309.

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

Scaffidi P and Misteli T (2005) Reversal of the cellular phenotype in the premature aging disease Hutchison‐Gilford progeria syndrome. Nature Medicine 11: 440–445.

Scaffidi P and Misteli T (2006) Lamin A‐dependent nuclear defects in human aging. Science 312: 1059–1063.

Scaffidi P and Misteli T (2008) Lamin A‐dependent misregulation of adult stem cells associated with accelerated ageing. Nature Cell Biology 10(4): 452–459.

Scheider R and Groschedl R (2007) Dynamics and interplay of nuclear architecture, genome organization, and gene expression. Genes & Development 21: 3027–3043.

Shimi T, Pfleghaar K and Kojima S (2008) The A‐ and B‐type nuclear lamin networks: microdomains involved in chromatin organization and transcription. Genes & Development 22: 3409–3421.

Shumaker DK, Dechat T and Kohlmaier A (2006) Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proceedings of the National Academy of Sciences of the USA 103: 8703–8708.

Toth JI, Yang SH, Qiao X et al. (2005) Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes. Proceedings of the National Academy of Sciences of the USA 102(36): 12873–12878.

Tsai MY, Wang S and Heidinger JM (2006) A mitotic lamin B matrix induced by RanGTP required for spindle assembly. Science 311(5769): 1887–1893.

Varela I, Pereira S and Ugalde AP (2008) Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nature Medicine 14(7): 767–772.

Verstraeten VL, Peckham LA, Olive M et al. (2011) Protein farnesylation inhibitors cause donut‐shaped cell nuclei attributable to a centrosome separation defect. Proceedings of the National Academy of Sciences of the USA 108(12): 4997–5002.

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

Young J, Morbois‐Trabut L and Couzinet B (2005) Type A insulin resistance syndrome revealing a novel lamin A mutation. Diabetes 54: 1873–1878.

Zhang J, Lian Q and Zhu G (2011) A human iPSC model of Hutchinson‐Gilford Progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell Stem Cell 8: 1–15.

Further Reading

Hernandez L, Roux KJ and Wong ES (2010) Functional coupling between the extracellular matrix and nuclear lamina in Wnt signaling in progeria. Developmental Cell 19: 413–425.

Hetzer MW and Wente SR (2009) Border control at the nucleus: biogenesis and organization of the nuclear membrane and pore complexes. Developmental Cell 17: 606–616.

Lusk CP, Blobel G and King MC (2007) Highway to the inner nuclear membrane: rules for the road. Nature Reviews Molecular Cell Biology 8: 414–420.

Parnaik VK, Chaturvedi P and Muralkrishna B (2011) Lamins, laminopathies and disease mechanisms: possible role for proteosomal degradation of key regulatory proteins. Journal of Bioscience 36(3): 471–479.

Ruis BL, Fattah KR and Hendrickson EA (2008) The catalytic subunit of DNA‐dependent protein kinase regulates proliferation, telomere length, and genomic stability in human somatic cells. Molecular Cell Biology 28(20): 6182–6195.

Schirmer EC and Gerace L (2005) The nuclear membrane proteome: extending the envelope. Trends in Biochemical Science 30: 551–558.

Stuurman N, Heins S and Aebi U (1998) Nuclear lamins: their structure, assembly and interactions. Journal of Structural Biology 122: 42–66.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Cao, Kan(Jul 2012) Cellular Basis of Laminopathies. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022533]