1932

Abstract

The nuclear envelope is composed of the nuclear membranes, nuclear lamina, and nuclear pore complexes. Laminopathies are diseases caused by mutations in genes encoding protein components of the lamina and these other nuclear envelope substructures. Mutations in the single gene encoding lamin A and C, which are expressed in most differentiated somatic cells, cause diseases affecting striated muscle, adipose tissue, peripheral nerve, and multiple systems with features of accelerated aging. Mutations in genes encoding other nuclear envelope proteins also cause an array of diseases that selectively affect different tissues or organs. In some instances, the molecular and cellular consequences of laminopathy-causing mutations are known. However, even when these are understood, mechanisms explaining specific tissue or organ pathology remain enigmatic. Current mechanistic hypotheses focus on how alterations in the nuclear envelope may affect gene expression, including via the regulation of signaling pathways, or cellular mechanics, including responses to mechanical stress.

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2022-01-24
2024-03-28
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Literature Cited

  1. 1. 
    Bione S, Maestrini E, Rivella S, Mancini M, Regis S et al. 1994. Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nat. Genet. 8:323–27
    [Google Scholar]
  2. 2. 
    Nagano A, Koga R, Ogawa M, Kurano Y, Kawada J et al. 1996. Emerin deficiency at the nuclear membrane in patients with Emery-Dreifuss muscular dystrophy. Nat. Genet. 12:254–59
    [Google Scholar]
  3. 3. 
    Manilal S, Nguyen TM, Sewry CA, Morris GE. 1996. The Emery-Dreifuss muscular dystrophy protein, emerin, is a nuclear membrane protein. Hum. Mol. Genet. 5:801–8
    [Google Scholar]
  4. 4. 
    Bonne G, Di Barletta MR, Varnous S, Becane HM, Hammouda EH et al. 1999. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat. Genet. 21:285–88
    [Google Scholar]
  5. 5. 
    Cao H, Hegele RA. 2000. Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum. Mol. Genet. 9:109–12
    [Google Scholar]
  6. 6. 
    Shackleton S, Lloyd DJ, Jackson SN, Evans R, Niermeijer MF et al. 2000. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat. Genet. 24:153–56
    [Google Scholar]
  7. 7. 
    Speckman RA, Garg A, Du F, Bennett L, Veile R et al. 2000. Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C. Am. J. Hum. Genet. 66:1192–98
    [Google Scholar]
  8. 8. 
    Novelli G, Muchir A, Sangiuolo F, Helbling-Leclerc A, D'Apice MR et al. 2002. Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am. J. Hum. Genet. 71:426–31
    [Google Scholar]
  9. 9. 
    De Sandre-Giovannoli A, Chaouch M, Kozlov S, Vallat J-M, Tazir M 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. Am. J. Hum. Genet. 70:726–36
    [Google Scholar]
  10. 10. 
    De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J et al. 2003. Lamin A truncation in Hutchinson-Gilford progeria. Science 300:2055
    [Google Scholar]
  11. 11. 
    Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J et al. 2003. Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 423:293–98
    [Google Scholar]
  12. 12. 
    Turgay Y, Eibauer M, Goldman AE, Shimi T, Khayat M et al. 2017. The molecular architecture of lamins in somatic cells. Nature 543:261–64
    [Google Scholar]
  13. 13. 
    Knockenhauer KE, Schwartz TU. 2016. The nuclear pore complex as a flexible and dynamic gate. Cell 164:1162–71
    [Google Scholar]
  14. 14. 
    Schirmer EC, Florens L, Guan T, Yates JR, Gerace L. 2003. Nuclear membrane proteins with potential disease links found by subtractive proteomics. Science 301:1380–82
    [Google Scholar]
  15. 15. 
    Soullam B, Worman HJ. 1995. Signals and structural features involved in integral membrane protein targeting to the inner nuclear membrane. J. Cell Biol. 130:15–27
    [Google Scholar]
  16. 16. 
    Crisp M, Liu Q, Roux K, Rattner J, Shanahan C et al. 2006. Coupling of the nucleus and cytoplasm: role of the LINC complex. J. Cell Biol. 172:41–53
    [Google Scholar]
  17. 17. 
    Sosa BA, Rothballer A, Kutay U, Schwartz TU. 2012. LINC complexes form by binding of three KASH peptides to domain interfaces of trimeric SUN proteins. Cell 149:1035–47
    [Google Scholar]
  18. 18. 
    Gundersen GG, Worman HJ. 2013. Nuclear positioning. Cell 152:1376–89
    [Google Scholar]
  19. 19. 
    Rober R-A, 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 105:365–78
    [Google Scholar]
  20. 20. 
    Korfali N, Wilkie GS, Swanson SK, Srsen V, de Las Heras J et al. 2012. The nuclear envelope proteome differs notably between tissues. Nucleus 3:552–64
    [Google Scholar]
  21. 21. 
    Lin F, Worman HJ 1993. Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C. J. Biol. Chem. 268:16321–26
    [Google Scholar]
  22. 22. 
    Wydner KL, McNeil JA, Lin F, Worman HJ, Lawrence JB. 1996. Chromosomal assignment of human nuclear envelope protein genes LMNA, LMNB1, and LBR by fluorescence in situ hybridization. Genomics 32:474–78
    [Google Scholar]
  23. 23. 
    Young SG, Fong LG, Michaelis S. 2005. Prelamin A, Zmpste24, misshapen cell nuclei, and progeria—new evidence suggesting that protein farnesylation could be important for disease pathogenesis. J. Lipid Res. 46:2531–58
    [Google Scholar]
  24. 24. 
    Marcelot A, Worman HJ, Zinn-Justin S. 2021. Protein structural and mechanistic basis of progeroid laminopathies. FEBS J 288:2757–72
    [Google Scholar]
  25. 25. 
    Merideth MA, Gordon LB, Clauss S, Sachdev V, Smith AC et al. 2008. Phenotype and course of Hutchinson–Gilford progeria syndrome. N. Engl. J. Med. 358:592–604
    [Google Scholar]
  26. 26. 
    Wang Y, Lichter-Konecki U, Anyane-Yeboa K, Shaw JE, Lu JT et al. 2016. A mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder. J. Cell Sci. 129:1975–80
    [Google Scholar]
  27. 27. 
    Barrowman J, Wiley PA, Hudon-Miller SE, Hrycyna CA, Michaelis S 2012. Human ZMPSTE24 disease mutations: Residual proteolytic activity correlates with disease severity. Hum. Mol. Genet. 21:4084–93
    [Google Scholar]
  28. 28. 
    Moulson CL, Go G, Gardner JM, van der Wal AC, Smitt JHS et al. 2005. Homozygous and compound heterozygous mutations in ZMPSTE24 cause the laminopathy restrictive dermopathy. J. Investig. Dermatol. 125:913–19
    [Google Scholar]
  29. 29. 
    Navarro CL, Cadinanos J, Sandre-Giovannoli AD, Bernard R, Courrier S et al. 2005. Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors. Hum. Mol. Genet. 14:1503–13
    [Google Scholar]
  30. 30. 
    Goldman RD, Shumaker DK, Erdos MR, Eriksson M, Goldman AE et al. 2004. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome. PNAS 101:8963–68
    [Google Scholar]
  31. 31. 
    Yang SH, Bergo MO, Toth JI, Qiao X, Hu Y et al. 2005. Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson–Gilford progeria syndrome mutation. PNAS 102:10291–96
    [Google Scholar]
  32. 32. 
    Toth JI, Yang SH, Qiao X, Beigneux AP, Gelb MH et al. 2005. Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes. PNAS 102:12873–78
    [Google Scholar]
  33. 33. 
    Capell BC, Erdos MR, Madigan JP, Fiordalisi JJ, Varga R et al. 2005. Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. PNAS 102:12879–84
    [Google Scholar]
  34. 34. 
    Glynn MW, Glover TW. 2005. Incomplete processing of mutant lamin A in Hutchinson–Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Hum. Mol. Genet. 14:2959–69
    [Google Scholar]
  35. 35. 
    Mallampalli MP, Huyer G, Bendale P, Gelb MH, Michaelis S. 2005. Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome. PNAS 102:14416–21
    [Google Scholar]
  36. 36. 
    Wang Y, Östlund C, Worman H. 2010. Blocking protein farnesylation improves nuclear shape abnormalities in keratinocytes of mice expressing the prelamin A variant in Hutchinson-Gilford progeria syndrome. Nucleus 1:432–39
    [Google Scholar]
  37. 37. 
    Fong LG, Frost D, Meta M, Qiao X, Yang SH et al. 2006. A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Science 311:1621–23
    [Google Scholar]
  38. 38. 
    Yang SH, Meta M, Qiao X, Frost D, Bauch J et al. 2006. A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation. J. Clin. Investig. 116:2115–21
    [Google Scholar]
  39. 39. 
    Capell BC, Olive M, Erdos MR, Cao K, Faddah DA et al. 2008. A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model. PNAS 105:15902–7
    [Google Scholar]
  40. 40. 
    Varela I, Pereira S, Ugalde AP, Navarro CL, Suárez MF et al. 2008. Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat. Med. 14:767–72
    [Google Scholar]
  41. 41. 
    Gordon LB, Kleinman ME, Miller DT, Neuberg DS, Giobbie-Hurder A et al. 2012. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome. PNAS 109:16666–71
    [Google Scholar]
  42. 42. 
    Mullard A. 2021. The FDA approves a first farnesyltransferase inhibitor. Nat. Rev. Drug Discov. 20:8
    [Google Scholar]
  43. 43. 
    Verstraeten VL, Ji JY, Cummings KS, Lee RT, Lammerding J 2008. Increased mechanosensitivity and nuclear stiffness in Hutchinson-Gilford progeria cells: effects of farnesyltransferase inhibitors. Aging Cell 7:383–93
    [Google Scholar]
  44. 44. 
    Liu B, Wang J, Chan KM, Tjia WM, Deng W et al. 2005. Genomic instability in laminopathy-based premature aging. Nat. Med. 11:780–85
    [Google Scholar]
  45. 45. 
    Kreienkamp R, Graziano S, Coll-Bonfill N, Bedia-Diaz G, Cybulla E et al. 2018. A cell-intrinsic interferon-like response links replication stress to cellular aging caused by progerin. Cell Rep. 22:2006–15
    [Google Scholar]
  46. 46. 
    Liu GH, Barkho BZ, Ruiz S, Diep D, Qu J et al. 2011. Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature 472:221–25
    [Google Scholar]
  47. 47. 
    Chen L, Lee L, Kudlow BA, Dos Santos HG, Sletvold O et al. 2003. LMNA mutations in atypical Werner's syndrome. Lancet 362:440–45
    [Google Scholar]
  48. 48. 
    Samson C, Petitalot A, Celli F, Herrada I, Ropars V et al. 2018. Structural analysis of the ternary complex between lamin A/C, BAF and emerin identifies an interface disrupted in autosomal recessive progeroid diseases. Nucleic Acids Res 46:10460–73
    [Google Scholar]
  49. 49. 
    Puente XS, Quesada V, Osorio FG, Cabanillas R, Cadiñanos J et al. 2011. Exome sequencing and functional analysis identifies BANF1 mutation as the cause of a hereditary progeroid syndrome. Am. J. Hum. Genet. 88:650–56
    [Google Scholar]
  50. 50. 
    Sears RM, Roux KJ. 2020. Diverse cellular functions of barrier-to-autointegration factor and its roles in disease. J. Cell Sci. 133:jcs246546
    [Google Scholar]
  51. 51. 
    Emery AE 2000. Emery–Dreifuss muscular dystrophy—a 40 year retrospective. Neuromuscul. Disord. 10:228–32
    [Google Scholar]
  52. 52. 
    Fatkin D, MacRae C, Sasaki T, Wolff MR, Porcu M et al. 1999. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N. Engl. J. Med. 341:1715–24
    [Google Scholar]
  53. 53. 
    Muchir A, Bonne G, van der Kooi AJ, van Meegen M, Baas F 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). Hum. Mol. Genet. 9:1453–59
    [Google Scholar]
  54. 54. 
    Bonne G, Mercuri E, Muchir A, Urtizberea A, Becane HM et al. 2000. Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene. Ann. Neurol. 48:170–80
    [Google Scholar]
  55. 55. 
    Raffaele Di Barletta M, Ricci E, Galluzzi G, Tonali P, Mora M et al. 2000. Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy. Am. J. Hum. Genet. 66:1407–12
    [Google Scholar]
  56. 56. 
    Brodsky GL, Muntoni F, Miocic S, Sinagra G, Sewry C et al. 2000. Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement. Circulation 101:473–76
    [Google Scholar]
  57. 57. 
    Quijano-Roy S, Mbieleu B, Bönnemann CG, Jeannet PY, Colomer J et al. 2008. De novo LMNA mutations cause a new form of congenital muscular dystrophy. Ann. Neurol. 64:177–86
    [Google Scholar]
  58. 58. 
    Jimenez-Escrig A, Gobernado I, Garcia-Villanueva M, Sanchez-Herranz A. 2012. Autosomal recessive Emery–Dreifuss muscular dystrophy caused by a novel mutation (R225Q) in the lamin A/C gene identified by exome sequencing. Muscle Nerve 45:605–10
    [Google Scholar]
  59. 59. 
    Sullivan T, Escalante-Alcalde D, Bhatt H, Anver M, Bhat N et al. 1999. Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. J. Cell Biol. 147:913–20
    [Google Scholar]
  60. 60. 
    Muchir A, Medioni J, Laluc M, Massart C, Arimura T et al. 2004. Nuclear envelope alterations in fibroblasts from patients with muscular dystrophy, cardiomyopathy, and partial lipodystrophy carrying lamin A/C gene mutations. Muscle Nerve 30:444–50
    [Google Scholar]
  61. 61. 
    Lammerding J, Schulze PC, Takahashi T, Kozlov S, Sullivan T et al. 2004. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J. Clin. Investig. 113:370–78
    [Google Scholar]
  62. 62. 
    Folker ES, Östlund C, Luxton GG, Worman HJ, Gundersen GG. 2011. Lamin A variants that cause striated muscle disease are defective in anchoring transmembrane actin-associated nuclear lines for nuclear movement. PNAS 108:131–36
    [Google Scholar]
  63. 63. 
    Kronenberg-Tenga R, Tatli M, Eibauer M, Wu W, Shin J-Y et al. 2021. A lamin A/C variant causing striated muscle disease provides insights into filament organization. J. Cell Sci. 134:jcs256156
    [Google Scholar]
  64. 64. 
    Östlund C, Bonne G, Schwartz K, Worman HJ. 2001. Properties of lamin A mutants found in Emery-Dreifuss muscular dystrophy, cardiomyopathy and Dunnigan-type partial lipodystrophy. J. Cell Sci. 114:4435–45
    [Google Scholar]
  65. 65. 
    Raharjo WH, Enarson P, Sullivan T, Stewart CL, Burke B. 2001. Nuclear envelope defects associated with LMNA mutations cause dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy. J. Cell Sci. 114:4447–57
    [Google Scholar]
  66. 66. 
    Clements L, Manilal S, Love DR, Morris GE. 2000. Direct interaction between emerin and lamin A. Biochem. Biophys. Res. Commun. 267:709–14
    [Google Scholar]
  67. 67. 
    Shin JY, Mendez-Lopez I, Wang Y, Hays AP, Tanji K et al. 2013. Lamina-associated polypeptide-1 interacts with the muscular dystrophy protein emerin and is essential for skeletal muscle maintenance. Dev. Cell 26:591–603
    [Google Scholar]
  68. 68. 
    Shin JY, Le Dour C, Sera F, Iwata S, Homma S et al. 2014. Depletion of lamina-associated polypeptide 1 from cardiomyocytes causes cardiac dysfunction in mice. Nucleus 5:260–68
    [Google Scholar]
  69. 69. 
    Kayman-Kurekci G, Talim B, Korkusuz P, Sayar N, Sarioglu T et al. 2014. Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: a novel gene related to nuclear envelopathies. Neuromuscul. Disord. 24:624–33
    [Google Scholar]
  70. 70. 
    Dunnigan M, Cochrane M, Kelly A, Scott J 1974. Familial lipoatrophic diabetes with dominant transmission: a new syndrome. Quart. . J. Med. 43:33–48
    [Google Scholar]
  71. 71. 
    Vigouroux C, Magre J, Vantyghem M-C, Bourut C, Lascols O et al. 2000. Lamin A/C gene: sex-determined expression of mutations in Dunnigan-type familial partial lipodystrophy and absence of coding mutations in congenital and acquired generalized lipoatrophy. Diabetes 49:1958–62
    [Google Scholar]
  72. 72. 
    Lüdtke A, Genschel J, Brabant G, Bauditz J, Taupitz M et al. 2005. Hepatic steatosis in Dunnigan-type familial partial lipodystrophy. Am. J. Gastroenterol. 100:2218–24
    [Google Scholar]
  73. 73. 
    Decaudain A, Vantyghem MC, Guerci B, Hecart AC, Auclair M et al. 2007. New metabolic phenotypes in laminopathies: LMNA mutations in patients with severe metabolic syndrome. J. Clin. Endocrinol. Metab. 92:4835–44
    [Google Scholar]
  74. 74. 
    Dhe-Paganon S, Werner ED, Chi Y-I, Shoelson SE. 2002. Structure of the globular tail of nuclear lamin. J. Biol. Chem. 277:17381–84
    [Google Scholar]
  75. 75. 
    Krimm I, Östlund C, Gilquin B, Couprie J, Hossenlopp P et al. 2002. The Ig-like structure of the C-terminal domain of lamin A/C, mutated in muscular dystrophies, cardiomyopathy, and partial lipodystrophy. Structure 10:811–23
    [Google Scholar]
  76. 76. 
    Lloyd DJ, Trembath RC, Shackleton S. 2002. A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies. Hum. Mol. Genet. 11:769–77
    [Google Scholar]
  77. 77. 
    Vadrot N, Duband-Goulet I, Cabet E, Attanda W, Barateau A et al. 2015. The p.R482W substitution in A-type lamins deregulates SREBP1 activity in Dunnigan-type familial partial lipodystrophy. Hum. Mol. Genet. 24:2096–109
    [Google Scholar]
  78. 78. 
    Boguslavsky RL, Stewart CL, Worman HJ. 2006. Nuclear lamin A inhibits adipocyte differentiation: implications for Dunnigan-type familial partial lipodystrophy. Hum. Mol. Genet. 15:653–63
    [Google Scholar]
  79. 79. 
    Tazir M, Azzedine H, Assami S, Sindou P, Nouioua S et al. 2004. Phenotypic variability in autosomal recessive axonal Charcot–Marie–Tooth disease due to the R298C mutation in lamin A/C. Brain 127:154–63
    [Google Scholar]
  80. 80. 
    Poitelon Y, Kozlov S, Devaux J, Vallat J-M, Jamon M et al. 2012. Behavioral and molecular exploration of the AR-CMT2A mouse model Lmna R298C/R298C. Neuromol. Med. 14:40–52
    [Google Scholar]
  81. 81. 
    Coffinier C, Chang SY, Nobumori C, Tu Y, Farber EA et al. 2010. Abnormal development of the cerebral cortex and cerebellum in the setting of lamin B2 deficiency. PNAS 107:5076–81
    [Google Scholar]
  82. 82. 
    Coffinier C, Jung H-J, Nobumori C, Chang S, Tu Y et al. 2011. Deficiencies in lamin B1 and lamin B2 cause neurodevelopmental defects and distinct nuclear shape abnormalities in neurons. Mol. Biol. Cell 22:4683–93
    [Google Scholar]
  83. 83. 
    Cristofoli F, Moss T, Moore HW, Devriendt K, Flanagan-Steet H et al. 2020. De novo variants in LMNB1 cause pronounced syndromic microcephaly and disruption of nuclear envelope integrity. Am. J. Hum. Genet. 107:753–62
    [Google Scholar]
  84. 84. 
    Parry DA, Martin C-A, Greene P, Marsh JA, Blyth M et al. 2021. Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy. Genet. Med. 23:408–14
    [Google Scholar]
  85. 85. 
    Padiath QS, Saigoh K, Schiffmann R, Asahara H, Yamada T et al. 2006. Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat. Genet. 38:1114–23
    [Google Scholar]
  86. 86. 
    Heng MY, Lin S-T, Verret L, Huang Y, Kamiya S et al. 2013. Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model. J. Clin. Investig. 123:2719–29
    [Google Scholar]
  87. 87. 
    Manilal S, Recan D, Sewry CA, Hoeltzenbein M, Llense S et al. 1998. Mutations in Emery-Dreifuss muscular dystrophy and their effects on emerin protein expression. Hum. Mol. Genet. 7:855–64
    [Google Scholar]
  88. 88. 
    Yates JR, Bagshaw J, Aksmanovic VM, Coomber E, McMahon R et al. 1999. Genotype-phenotype analysis in X-linked Emery–Dreifuss muscular dystrophy and identification of a missense mutation associated with a milder phenotype. Neuromuscul. Disord. 9:159–65
    [Google Scholar]
  89. 89. 
    Muntoni F, Lichtarowicz-Krynska EJ, Sewry CA, Manilal S, Recan D et al. 1998. Early presentation of X-linked Emery–Dreifuss muscular dystrophy resembling limb-girdle muscular dystrophy. Neuromuscul. Disord. 8:72–76
    [Google Scholar]
  90. 90. 
    Astejada M, Goto K, Nagano A, Ura S, Noguchi S et al. 2007. Emerinopathy and laminopathy clinical, pathological and molecular features of muscular dystrophy with nuclear envelopathy in Japan. Acta Myol 26:159–64
    [Google Scholar]
  91. 91. 
    Muchir A, Pavlidis P, Decostre V, Herron AJ, Arimura T et al. 2007. Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy. J. Clin. Investig. 117:1282–93
    [Google Scholar]
  92. 92. 
    Muchir A, Wu W, Worman HJ. 2009. Reduced expression of A-type lamins and emerin activates extracellular signal-regulated kinase in cultured cells. Biochim. Biophys. Acta Mol. Basis Dis. 1792:75–81
    [Google Scholar]
  93. 93. 
    Muchir A, Pavlidis P, Bonne G, Hayashi YK, Worman HJ. 2007. Activation of MAPK in hearts of EMD null mice: similarities between mouse models of X-linked and autosomal dominant Emery Dreifuss muscular dystrophy. Hum. Mol. Genet. 16:1884–95
    [Google Scholar]
  94. 94. 
    Melcon G, Kozlov S, Cutler DA, Sullivan T, Hernandez L et al. 2006. Loss of emerin at the nuclear envelope disrupts the Rb1/E2F and MyoD pathways during muscle regeneration. Hum. Mol. Genet. 15:637–51
    [Google Scholar]
  95. 95. 
    Ozawa R, Hayashi YK, Ogawa M, Kurokawa R, Matsumoto H et al. 2006. Emerin-lacking mice show minimal motor and cardiac dysfunctions with nuclear-associated vacuoles. Am. J. Pathol. 168:907–17
    [Google Scholar]
  96. 96. 
    Lin F, Blake DL, Callebaut I, Skerjanc IS, Holmer L et al. 2000. MAN1, an inner nuclear membrane protein that shares the LEM domain with lamina-associated polypeptide 2 and emerin. J. Biol. Chem. 275:4840–47
    [Google Scholar]
  97. 97. 
    Paulin-Levasseur M, Blake DL, Julien M, Rouleau L 1996. The MAN antigens are non-lamin constituents of the nuclear lamina in vertebrate cells. Chromosoma 104:367–79
    [Google Scholar]
  98. 98. 
    Hellemans J, Preobrazhenska O, Willaert A, Debeer P, Verdonk PC et al. 2004. Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat. Genet. 36:1213–18
    [Google Scholar]
  99. 99. 
    Lin F, Morrison JM, Wu W, Worman HJ. 2005. MAN1, an integral protein of the inner nuclear membrane, binds Smad2 and Smad3 and antagonizes transforming growth factor-β signaling. Hum. Mol. Genet. 14:437–45
    [Google Scholar]
  100. 100. 
    Pan D, Estévez-Salmerón LD, Stroschein SL, Zhu X, He J et al. 2005. The integral inner nuclear membrane protein MAN1 physically interacts with the R-Smad proteins to repress signaling by the transforming growth factor-β superfamily of cytokines. J. Biol. Chem. 280:15992–6001
    [Google Scholar]
  101. 101. 
    Ishimura A, Ng JK, Taira M, Young SG, Osada S-I. 2006. Man1, an inner nuclear membrane protein, regulates vascular remodeling by modulating transforming growth factor β signaling. Development 133:3919–28
    [Google Scholar]
  102. 102. 
    Cohen TV, Kosti O, Stewart CL. 2007. The nuclear envelope protein MAN1 regulates TGFβ signaling and vasculogenesis in the embryonic yolk sac. Development 134:1385–95
    [Google Scholar]
  103. 103. 
    Bourgeois B, Gilquin B, Tellier-Lebègue C, Östlund C, Wu W et al. 2013. Inhibition of TGF-β signaling at the nuclear envelope: characterization of interactions between MAN1, Smad2 and Smad3, and PPM1A. Sci. Signal. 6:ra49
    [Google Scholar]
  104. 104. 
    Worman HJ, Yuan J, Blobel G, Georgatos SD. 1988. A lamin B receptor in the nuclear envelope. PNAS 85:8531–34
    [Google Scholar]
  105. 105. 
    Worman HJ, Evans CD, Blobel G. 1990. The lamin B receptor of the nuclear envelope inner membrane: a polytopic protein with eight potential transmembrane domains. J. Cell Biol. 111:1535–42
    [Google Scholar]
  106. 106. 
    Ye Q, Worman HJ 1996. Interaction between an integral protein of the nuclear envelope inner membrane and human chromodomain proteins homologous to Drosophila HP1. J. Biol. Chem. 271:14653–56
    [Google Scholar]
  107. 107. 
    Holmer L, Pezhman A, Worman HJ. 1998. The human lamin B receptor/sterol reductase multigene family. Genomics 54:469–76
    [Google Scholar]
  108. 108. 
    Hoffmann K, Dreger CK, Olins AL, Olins DE, Shultz LD et al. 2002. Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger–Huet anomaly). Nat. Genet. 31:410–14
    [Google Scholar]
  109. 109. 
    Waterham HR, Koster J, Mooyer P, van Noort G, Kelley RI et al. 2003. Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3β-hydroxysterol Δ14-reductase deficiency due to mutations in the lamin B receptor gene. Am. J. Med. Genet. 72:1013–17
    [Google Scholar]
  110. 110. 
    Clayton P, Fischer B, Mann A, Mansour S, Rossier E et al. 2010. Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein. Nucleus 1:354–66
    [Google Scholar]
  111. 111. 
    Tsai P-L, Zhao C, Turner E, Schlieker C 2016. The Lamin B receptor is essential for cholesterol synthesis and perturbed by disease-causing mutations. eLife 5:e16011
    [Google Scholar]
  112. 112. 
    Shultz LD, Lyons BL, Burzenski LM, Gott B, Samuels R et al. 2003. Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger–Huet anomaly. Hum. Mol. Genet. 12:61–69
    [Google Scholar]
  113. 113. 
    Cohen TV, Klarmann KD, Sakchaisri K, Cooper JP, Kuhns D et al. 2008. The lamin B receptor under transcriptional control of C/EBPε is required for morphological but not functional maturation of neutrophils. Hum. Mol. Genet. 17:2921–33
    [Google Scholar]
  114. 114. 
    Bengtsson L, Otto H. 2008. LUMA interacts with emerin and influences its distribution at the inner nuclear membrane. J. Cell Sci. 121:536–48
    [Google Scholar]
  115. 115. 
    Merner ND, Hodgkinson KA, Haywood AF, Connors S, French VM et al. 2008. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am. J. Hum. Genet. 82:809–21
    [Google Scholar]
  116. 116. 
    Stroud MJ, Fang X, Zhang J, Guimarães-Camboa N, Veevers J et al. 2018. Luma is not essential for murine cardiac development and function. Cardiovasc. Res. 114:378–88
    [Google Scholar]
  117. 117. 
    Padrón-Barthe L, Villalba-Orero M, Gómez-Salinero JM, Domínguez F, Román M et al. 2019. Severe cardiac dysfunction and death caused by arrhythmogenic right ventricular cardiomyopathy type 5 are improved by inhibition of glycogen synthase kinase-3β. Circulation 140:1188–204
    [Google Scholar]
  118. 118. 
    Senior A, Gerace L. 1988. Integral membrane proteins specific to the inner nuclear membrane and associated with the nuclear lamina. J. Cell Biol. 107:2029–36
    [Google Scholar]
  119. 119. 
    Foisner R, Gerace L. 1993. Integral membrane proteins of the nuclear envelope interact with lamins and chromosomes, and binding is modulated by mitotic phosphorylation. Cell 73:1267–79
    [Google Scholar]
  120. 120. 
    Santos M, Domingues SC, Costa P, Muller T, Galozzi S et al. 2014. Identification of a novel human LAP1 isoform that is regulated by protein phosphorylation. PLOS ONE 9:e113732
    [Google Scholar]
  121. 121. 
    Martin L, Crimaudo C, Gerace L. 1995. cDNA cloning and characterization of lamina-associated polypeptide 1C (LAP1C), an integral protein of the inner nuclear membrane. J. Biol. Chem. 270:8822–28
    [Google Scholar]
  122. 122. 
    Zhao C, Brown RS, Chase AR, Eisele MR, Schlieker C. 2013. Regulation of torsin ATPases by LAP1 and LULL1. PNAS 110:E1545–54
    [Google Scholar]
  123. 123. 
    Sosa BA, Demircioglu FE, Chen JZ, Ingram J, Ploegh HL et al. 2014. How lamina-associated polypeptide 1 (LAP1) activates Torsin. eLife 3:e03239
    [Google Scholar]
  124. 124. 
    Goodchild RE, Dauer WT. 2005. The AAA+ protein torsinA interacts with a conserved domain present in LAP1 and a novel ER protein. J. Cell Biol. 168:855–62
    [Google Scholar]
  125. 125. 
    Shin J-Y, Méndez-López I, Hong M, Wang Y, Tanji K et al. 2017. Lamina-associated polypeptide 1 is dispensable for embryonic myogenesis but required for postnatal skeletal muscle growth. Hum. Mol. Genet. 26:65–78
    [Google Scholar]
  126. 126. 
    Fichtman B, Zagairy F, Biran N, Barsheshet Y, Chervinsky E et al. 2019. Combined loss of LAP1B and LAP1C results in an early onset multisystemic nuclear envelopathy. Nat. Commun. 10:605
    [Google Scholar]
  127. 127. 
    Brachner A, Reipert S, Foisner R, Gotzmann J. 2005. LEM2 is a novel MAN1-related inner nuclear membrane protein associated with A-type lamins. J. Cell Sci. 118:5797–810
    [Google Scholar]
  128. 128. 
    Halfmann CT, Sears RM, Katiyar A, Busselman BW, Aman LK et al. 2019. Repair of nuclear ruptures requires barrier-to-autointegration factor. J. Cell Biol. 218:2136–49
    [Google Scholar]
  129. 129. 
    von Appen A, LaJoie D, Johnson IE, Trnka MJ, Pick SM et al. 2020. LEM2 phase separation promotes ESCRT-mediated nuclear envelope reformation. Nature 582:115–18
    [Google Scholar]
  130. 130. 
    Huber MD, Guan T, Gerace L 2009. Overlapping functions of nuclear envelope proteins NET25 (Lem2) and emerin in regulation of ERK signaling in myoblast differentiation. Mol. Cell. Biol. 29:5718–28
    [Google Scholar]
  131. 131. 
    Marbach F, Rustad CF, Riess A, Đukić D, Hsieh T-C et al. 2019. The discovery of a LEMD2-associated nuclear envelopathy with early progeroid appearance suggests advanced applications for AI-driven facial phenotyping. Am. J. Hum. Genet. 104:749–57
    [Google Scholar]
  132. 132. 
    Meinke P, Mattioli E, Haque F, Antoku S, Columbaro M et al. 2014. Muscular dystrophy-associated SUN1 and SUN2 variants disrupt nuclear-cytoskeletal connections and myonuclear organization. PLOS Genet 10:e1004605
    [Google Scholar]
  133. 133. 
    Gros-Louis F, Dupré N, Dion P, Fox MA, Laurent S et al. 2007. Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia. Nat. Genet. 39:80–85
    [Google Scholar]
  134. 134. 
    Attali R, Warwar N, Israel A, Gurt I, McNally E et al. 2009. Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis. Hum. Mol. Genet. 18:3462–69
    [Google Scholar]
  135. 135. 
    Banerjee I, Zhang J, Moore-Morris T, Pfeiffer E, Buchholz KS et al. 2014. Targeted ablation of nesprin 1 and nesprin 2 from murine myocardium results in cardiomyopathy, altered nuclear morphology and inhibition of the biomechanical gene response. PLOS Genet 10:e1004114
    [Google Scholar]
  136. 136. 
    Puckelwartz MJ, Kessler E, Zhang Y, Hodzic D, Randles KN et al. 2009. Disruption of nesprin-1 produces an Emery Dreifuss muscular dystrophy-like phenotype in mice. Hum. Mol. Genet. 18:607–20
    [Google Scholar]
  137. 137. 
    Zhang J, Felder A, Liu Y, Guo LT, Lange S et al. 2010. Nesprin 1 is critical for nuclear positioning and anchorage. Hum. Mol. Genet. 19:329–41
    [Google Scholar]
  138. 138. 
    Zhang Q, Bethmann C, Worth NF, Davies JD, Wasner C et al. 2007. Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity. Hum. Mol. Genet. 16:2816–33
    [Google Scholar]
  139. 139. 
    Puckelwartz MJ, Kessler EJ, Kim G, Dewitt MM, Zhang Y et al. 2010. Nesprin-1 mutations in human and murine cardiomyopathy. J. Mol. Cell. Cardiol. 48:600–8
    [Google Scholar]
  140. 140. 
    Zhou C, Li C, Zhou B, Sun H, Koullourou V et al. 2017. Novel nesprin-1 mutations associated with dilated cardiomyopathy cause nuclear envelope disruption and defects in myogenesis. Hum. Mol. Genet. 26:2258–76
    [Google Scholar]
  141. 141. 
    Horn HF, Brownstein Z, Lenz DR, Shivatzki S, Dror AA et al. 2013. The LINC complex is essential for hearing. J. Clin. Investig. 123:740–50
    [Google Scholar]
  142. 142. 
    Ozelius LJ, Hewett JW, Page CE, Bressman SB, Kramer PL et al. 1997. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat. Genet. 17:40–48
    [Google Scholar]
  143. 143. 
    Goodchild RE, Dauer WT. 2004. Mislocalization to the nuclear envelope: an effect of the dystonia-causing torsinA mutation. PNAS 101:847–52
    [Google Scholar]
  144. 144. 
    Naismith TV, Dalal S, Hanson PI 2009. Interaction of torsinA with its major binding partners is impaired by the dystonia-associated ΔGAG deletion. J. Biol. Chem. 284:27866–74
    [Google Scholar]
  145. 145. 
    Shashidharan P, Sandu D, Potla U, Armata I, Walker R et al. 2005. Transgenic mouse model of early-onset DYT1 dystonia. Hum. Mol. Genet. 14:125–33
    [Google Scholar]
  146. 146. 
    Goodchild RE, Kim CE, Dauer WT. 2005. Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope. Neuron 48:923–32
    [Google Scholar]
  147. 147. 
    Liang CC, Tanabe LM, Jou S, Chi F, Dauer WT 2014. TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration. J. Clin. Investig. 124:3080–92
    [Google Scholar]
  148. 148. 
    Pappas SS, Darr K, Holley SM, Cepeda C, Mabrouk OS et al. 2015. Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons. eLife 4:e08352
    [Google Scholar]
  149. 149. 
    Li J, Levin DS, Kim AJ, Pappas SS, Dauer WT. 2021. TorsinA restoration in a mouse model identifies a critical therapeutic window for DYT1 dystonia. J. Clin. Investig. 131:e139606
    [Google Scholar]
  150. 150. 
    Shin JY, Hernandez-Ono A, Fedotova T, Ostlund C, Lee MJ et al. 2019. Nuclear envelope-localized torsinA-LAP1 complex regulates hepatic VLDL secretion and steatosis. J. Clin. Investig. 130:4885–900
    [Google Scholar]
  151. 151. 
    Wente SR, Rout MP. 2010. The nuclear pore complex and nuclear transport. Cold Spring Harb. Perspect. Biol. 2:a000562
    [Google Scholar]
  152. 152. 
    Ibarra A, Hetzer MW. 2015. Nuclear pore proteins and the control of genome functions. Genes Dev. 29:337–49
    [Google Scholar]
  153. 153. 
    Nofrini V, Di Giacomo, D, Mecucci C. 2016. Nucleoporin genes in human diseases. Eur. J. Hum. Genet. 24:1388–95
    [Google Scholar]
  154. 154. 
    Jühlen R, Fahrenkrog B. 2018. Moonlighting nuclear pore proteins: tissue-specific nucleoporin function in health and disease. Histochem. Cell Biol 150:593–605
    [Google Scholar]
  155. 155. 
    Baylink DJ, Finkelman RD, Mohan S. 1993. Growth factors to stimulate bone formation. J. Bone Miner. Res 8:S565–72
    [Google Scholar]
  156. 156. 
    Blobel G. 1985. Gene gating: a hypothesis. PNAS 82:8527–29
    [Google Scholar]
  157. 157. 
    Kim PH, Luu J, Heizer P, Tu Y, Weston TA et al. 2018. Disrupting the LINC complex in smooth muscle cells reduces aortic disease in a mouse model of Hutchinson-Gilford progeria syndrome. Sci. Transl. Med. 10:eaat7163
    [Google Scholar]
  158. 158. 
    Earle AJ, Kirby TJ, Fedorchak GR, Isermann P, Patel J et al. 2020. Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells. Nat. Mater. 19:464–73
    [Google Scholar]
  159. 159. 
    Chen NY, Kim P, Weston TA, Edillo L, Tu Y et al. 2018. Fibroblasts lacking nuclear lamins do not have nuclear blebs or protrusions but nevertheless have frequent nuclear membrane ruptures. PNAS 115:10100–5
    [Google Scholar]
  160. 160. 
    Chen NY, Yang Y, Weston TA, Belling JN, Heizer P et al. 2019. An absence of lamin B1 in migrating neurons causes nuclear membrane ruptures and cell death. PNAS 116:25870–79
    [Google Scholar]
  161. 161. 
    Choi JC, Muchir A, Wu W, Iwata S, Homma S et al. 2012. Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation. Sci. Transl. Med. 4:144ra102
    [Google Scholar]
  162. 162. 
    Muchir A, Reilly SA, Wu W, Iwata S, Homma S et al. 2012. Treatment with selumetinib preserves cardiac function and improves survival in cardiomyopathy caused by mutation in the lamin A/C gene. Cardiovasc. Res. 93:311–19
    [Google Scholar]
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