Changes in the Nuclear Envelope in Laminopathies

  • Subarna Dutta
  • Maitree Bhattacharyya
  • Kaushik Sengupta
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1112)


Double-membrane-bound nucleus is the major organelle of every metazoan cell, which controls various nuclear processes like chromatin maintenance, DNA replication, transcription and nucleoskeleton-cytoskeleton coupling. Nuclear homeostasis depends on the integrity of nuclear membrane and associated proteins. Lamins, underlying the inner nuclear membrane (INM), play a crucial role in maintaining nuclear homeostasis. In this review, we have focussed on the disruption of nuclear homeostasis due to lamin A/C mutation which produces a plethora of diseases, termed as laminopathies.


Laminopathies Lamins Linker of nucleoskeleton and cytoskeleton Emerin Lamin B receptor Nuclear pore complex 


  1. Al-Haboubi T, Shumaker DK, Koser J, Wehnert M, Fahrenkrog B (2011) Distinct association of the nuclear pore protein Nup153 with A- and B-type lamins. Nucleus 2:500–509CrossRefGoogle Scholar
  2. Clayton P, Fischer B, Mann A, Mansour S, Rossier E, Veen M, Lang C, Baasanjav S, Kieslich M, Brossuleit K et al (2010) Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein. Nucleus 1:354–366CrossRefGoogle Scholar
  3. Daigle N, Beaudouin J, Hartnell L, Imreh G, Hallberg E, Lippincott-Schwartz J, Ellenberg J (2001) Nuclear pore complexes form immobile networks and have a very low turnover in live mammalian cells. J Cell Biol 154:71–84CrossRefGoogle Scholar
  4. Davies BS, Barnes RH 2nd, Tu Y, Ren S, Andres DA, Spielmann HP, Lammerding J, Wang Y, Young SG, Fong LG (2010) An accumulation of non-farnesylated prelamin A causes cardiomyopathy but not progeria. Hum Mol Genet 19:2682–2694CrossRefGoogle Scholar
  5. Davies BS, Coffinier C, Yang SH, Barnes RH 2nd, Jung HJ, Young SG, Fong LG (2011) Investigating the purpose of prelamin A processing. Nucleus 2:4–9CrossRefGoogle Scholar
  6. Dechat T, Pfleghaar K, Sengupta K, Shimi T, Shumaker DK, Solimando L, Goldman RD (2008) Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin. Genes Dev 22:832–853CrossRefGoogle Scholar
  7. Eibauer M, Pellanda M, Turgay Y, Dubrovsky A, Wild A, Medalia O (2015) Structure and gating of the nuclear pore complex. Nat Commun 6:7532CrossRefGoogle Scholar
  8. Fidzianska A, Bilinska ZT, Tesson F, Wagner T, Walski M, Grzybowski J, Ruzyllo W, Hausmanowa-Petrusewicz I (2008) Obliteration of cardiomyocyte nuclear architecture in a patient with LMNA gene mutation. J Neurol Sci 271:91–96CrossRefGoogle Scholar
  9. Gaines P, Tien CW, Olins AL, Olins DE, Shultz LD, Carney L, Berliner N (2008) Mouse neutrophils lacking Lamin B-receptor expression exhibit aberrant development and lack critical functional responses. Exp Hematol 36:965–976CrossRefGoogle Scholar
  10. Goldman RD, Shumaker DK, Erdos MR, Eriksson M, Goldman AE, Gordon LB, Gruenbaum Y, Khuon S, Mendez M, Varga R et al (2004) Accumulation of mutant Lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci USA 101:8963–8968CrossRefGoogle Scholar
  11. Grady RM, Starr DA, Ackerman GL, Sanes JR, Han M (2005) Syne proteins anchor muscle nuclei at the neuromuscular junction. Proc Natl Acad Sci USA 102:4359–4364CrossRefGoogle Scholar
  12. Gupta P, Bilinska ZT, Sylvius N, Boudreau E, Veinot JP, Labib S, Bolongo PM, Hamza A, Jackson T, Ploski R et al (2010) Genetic and ultrastructural studies in dilated cardiomyopathy patients: a large deletion in the Lamin A/C gene is associated with cardiomyocyte nuclear envelope disruption. Basic Res Cardiol 105:365–377CrossRefGoogle Scholar
  13. Hawryluk-Gara LA, Shibuya EK, Wozniak RW (2005) Vertebrate Nup53 interacts with the nuclear lamina and is required for the assembly of a Nup93-containing complex. Mol Biol Cell 16:2382–2394CrossRefGoogle Scholar
  14. Hegele RA, Cao H, Liu DM, Costain GA, Charlton-Menys V, Rodger NW, Durrington PN (2006) Sequencing of the reannotated LMNB2 gene reveals novel mutations in patients with acquired partial lipodystrophy. Am J Hum Genet 79:383–389CrossRefGoogle Scholar
  15. Hennekes H, Nigg EA (1994) The role of isoprenylation in membrane attachment of nuclear lamins. A single point mutation prevents proteolytic cleavage of the Lamin A precursor and confers membrane binding properties. J Cell Sci 107(Pt 4):1019–1029PubMedGoogle Scholar
  16. Hoffmann K, Dreger CK, Olins AL, Olins DE, Shultz LD, Lucke B, Karl H, Kaps R, Muller D, Vaya A et al (2002) Mutations in the gene encoding the Lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huet anomaly). Nat Genet 31:410–414CrossRefGoogle Scholar
  17. Holmer L, Pezhman A, Worman HJ (1998) The human Lamin B receptor/sterol reductase multigene family. Genomics 54:469–476CrossRefGoogle Scholar
  18. Houben F, Ramaekers FC, Snoeckx LH, Broers JL (2007) Role of nuclear lamina-cytoskeleton interactions in the maintenance of cellular strength. Biochim Biophys Acta 1773:675–686CrossRefGoogle Scholar
  19. Kelley K, Knockenhauer KE, Kabachinski G, Schwartz TU (2015) Atomic structure of the Y complex of the nuclear pore. Nat Struct Mol Biol 22:425–431CrossRefGoogle Scholar
  20. Lammerding J, Hsiao J, Schulze PC, Kozlov S, Stewart CL, Lee RT (2005) Abnormal nuclear shape and impaired mechanotransduction in emerin-deficient cells. J Cell Biol 170:781–791CrossRefGoogle Scholar
  21. Luke Y, Zaim H, Karakesisoglou I, Jaeger VM, Sellin L, Lu W, Schneider M, Neumann S, Beijer A, Munck M et al (2008) Nesprin-2 Giant (NUANCE) maintains nuclear envelope architecture and composition in skin. J Cell Sci 121:1887–1898CrossRefGoogle Scholar
  22. Lussi YC, Hugi I, Laurell E, Kutay U, Fahrenkrog B (2011) The nucleoporin Nup88 is interacting with nuclear Lamin A. Mol Biol Cell 22:1080–1090CrossRefGoogle Scholar
  23. Nikolakaki E, Meier J, Simos G, Georgatos SD, Giannakouros T (1997) Mitotic phosphorylation of the Lamin B receptor by a serine/arginine kinase and p34(cdc2). J Biol Chem 272:6208–6213CrossRefGoogle Scholar
  24. Padiath QS, Saigoh K, Schiffmann R, Asahara H, Yamada T, Koeppen A, Hogan K, Ptacek LJ, Fu YH (2006) Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat Genet 38:1114–1123CrossRefGoogle Scholar
  25. Pan Y, Garg A, Agarwal AK (2007) Mislocalization of prelamin A Tyr646Phe mutant to the nuclear pore complex in human embryonic kidney 293 cells. Biochem Biophys Res Commun 355:78–84CrossRefGoogle Scholar
  26. Rober RA, Weber K, Osborn M (1989) Differential timing of nuclear Lamin A/C expression in the various organs of the mouse embryo and the young animal: a developmental study. Development 105:365–378PubMedGoogle Scholar
  27. Rowat AC, Lammerding J, Ipsen JH (2006) Mechanical properties of the cell nucleus and the effect of emerin deficiency. Biophys J 91:4649–4664CrossRefGoogle Scholar
  28. Rusinol AE, Sinensky MS (2006) Farnesylated lamins, progeroid syndromes and farnesyl transferase inhibitors. J Cell Sci 119:3265–3272CrossRefGoogle Scholar
  29. Smythe C, Jenkins HE, Hutchison CJ (2000) Incorporation of the nuclear pore basket protein nup153 into nuclear pore structures is dependent upon lamina assembly: evidence from cell-free extracts of Xenopus eggs. EMBO J 19:3918–3931CrossRefGoogle Scholar
  30. Solovei I, Wang AS, Thanisch K, Schmidt CS, Krebs S, Zwerger M, Cohen TV, Devys D, Foisner R, Peichl L et al (2013) LBR and Lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation. Cell 152:584–598CrossRefGoogle Scholar
  31. Stegh AH, Herrmann H, Lampel S, Weisenberger D, Andra K, Seper M, Wiche G, Krammer PH, Peter ME (2000) Identification of the cytolinker plectin as a major early in vivo substrate for caspase 8 during CD95- and tumor necrosis factor receptor-mediated apoptosis. Mol Cell Biol 20:5665–5679CrossRefGoogle Scholar
  32. Stewart CL, Kozlov S, Fong LG, Young SG (2007) Mouse models of the laminopathies. Exp Cell Res 313:2144–2156CrossRefGoogle Scholar
  33. Suh Y, Kennedy BK (2012) Dialing down SUN1 for laminopathies. Cell 149:509–510CrossRefGoogle Scholar
  34. Sullivan T, Escalante-Alcalde D, Bhatt H, Anver M, Bhat N, Nagashima K, Stewart CL, Burke B (1999) Loss of A-type Lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. J Cell Biol 147:913–920CrossRefGoogle Scholar
  35. Talamas JA, Hetzer MW (2011) POM121 and Sun1 play a role in early steps of interphase NPC assembly. J Cell Biol 194:27–37CrossRefGoogle Scholar
  36. Tapley EC, Starr DA (2013) Connecting the nucleus to the cytoskeleton by SUN-KASH bridges across the nuclear envelope. Curr Opin Cell Biol 25:57–62CrossRefGoogle Scholar
  37. Ulbert S, Antonin W, Platani M, Mattaj IW (2006) The inner nuclear membrane protein Lem2 is critical for normal nuclear envelope morphology. FEBS Lett 580:6435–6441CrossRefGoogle Scholar
  38. Vargas JD, Hatch EM, Anderson DJ, Hetzer MW (2012) Transient nuclear envelope rupturing during interphase in human cancer cells. Nucleus 3:88–100CrossRefGoogle Scholar
  39. Vaughan A, Alvarez-Reyes M, Bridger JM, Broers JL, Ramaekers FC, Wehnert M, Morris GE, Whitfield WGF, Hutchison CJ (2001) Both emerin and Lamin C depend on Lamin A for localization at the nuclear envelope. J Cell Sci 114:2577–2590PubMedGoogle Scholar
  40. Vergnes L, Peterfy M, Bergo MO, Young SG, Reue K (2004) Lamin B1 is required for mouse development and nuclear integrity. Proc Natl Acad Sci USA 101:10428–10433CrossRefGoogle Scholar
  41. Vigouroux C, Auclair M, Dubosclard E, Pouchelet M, Capeau J, Courvalin JC, Buendia B (2001) Nuclear envelope disorganization in fibroblasts from lipodystrophic patients with heterozygous R482Q/W mutations in the Lamin A/C gene. J Cell Sci 114:4459–4468PubMedGoogle Scholar
  42. Yewdell WT, Colombi P, Makhnevych T, Lusk CP (2011) Lumenal interactions in nuclear pore complex assembly and stability. Mol Biol Cell 22:1375–1388CrossRefGoogle Scholar
  43. Zhang Q, Bethmann C, Worth NF, Davies JD, Wasner C, Feuer A, Ragnauth CD, Yi Q, Mellad JA, Warren DT et al (2007a) Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity. Hum Mol Genet 16:2816–2833CrossRefGoogle Scholar
  44. Zhang X, Xu R, Zhu B, Yang X, Ding X, Duan S, Xu T, Zhuang Y, Han M (2007b) Syne-1 and Syne-2 play crucial roles in myonuclear anchorage and motor neuron innervation. Development 134:901–908CrossRefGoogle Scholar
  45. Zhou Z, Du X, Cai Z, Song X, Zhang H, Mizuno T, Suzuki E, Yee MR, Berezov A, Murali R et al (2012) Structure of Sad1-UNC84 homology (SUN) domain defines features of molecular bridge in nuclear envelope. J Biol Chem 287:5317–5326CrossRefGoogle Scholar
  46. Zwerger M, Herrmann H, Gaines P, Olins AL, Olins DE (2008) Granulocytic nuclear differentiation of Lamin B receptor-deficient mouse EPRO cells. Exp Hematol 36:977–987CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Subarna Dutta
    • 1
    • 2
  • Maitree Bhattacharyya
    • 2
  • Kaushik Sengupta
    • 1
  1. 1.Biophysics & Structural Genomics DivisionSaha Institute of Nuclear PhysicsKolkataIndia
  2. 2.Department of BiochemistryUniversity of CalcuttaKolkataIndia

Personalised recommendations