2016


To access this material please log in or register

Register Authorize
2016/№3

The multidisciplinary and multisystemic issue of laminopathies: many diseases, one gene

Vaykhanskaya T. G.1, Sivitskaya L. N.2, Danilenko N. G.2, Kurushko T. V.1, Davydenko O. G.2
1 – State Institution Republican Science and Practice Center “Cardiology”, R. Luxemburg 110, Minsk 220036, Republic of Belarus
2 – State Science Institution, “Institute of Genetics and Cytology of Belarus National Academy of Sciences”, Akademicheskaya 27, Minsk 220072, Republic of Belarus

Keywords: laminopathies, lamin protein function, lamin a/c gene (lmna), dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy type IB, heart rhythm disturbances, conduction disorder, cardioverter-defibrillator

DOI: 10.18087/rhfj.2016.3.2223

Studies of the recent decade have significantly expanded the array of monogenic diseases associated with mutations in the la­min A/C gene (LMNA) which encodes a group of proteins performing important functions in the cell nucleus. This abnormality is characteri­zed by multiple systemic and tissue injuries, including cardiac phenotypes (dilated cardiomyopathy with or without muscular dystrophy), muscular dystrophies (Emery-Dreifuss, congenital, and limb-girdle muscular dystrophies), lipodystrophy (familial partial lipodystrophy, Kobberling and Dunnigan types), neuropathies (spinal and Charkot-Marie-Tooth type 2 neuropathies), progeroid phenotypes (mandibuloacral dysplasia, Hutchinson-Gilford progeria, atypical Werner syndrome), etc. The article presents an up-to-date review of literature and highlights major issues of laminopathies: epidemiology of muscular and cardiac phenotypes; lipodystrophy and progeria syndromes; structure and function of the lamin protein and the LMNA gene; pathophysio­logical and molecular biological mechanisms of the laminopathy pathogenesis; clinical manifestations, diagnostics and treatment of laminopathy cardiac phenotypes exampled by three case reports (dilated cardiomyopathy /DCMP/ type 1A with conduction defects; DCMP in combination with Emery-Dreifuss muscular dystrophy, and DCMP with limb-girdle muscular dystrophy type 1B). LMNA gene mutations are found in 6–10 % of patients with different DCMP types and in 30–33 % of patients with conduction defects. The lamin phenotype of cardiomyopathy is characterized by rapid progression of HF, early life-threatening arrhythmias, and a very high risk of sudden death, which justifies the need for preventive implantation of a pacemaker or a cardioverter-defibrillator.
  1. Worman HJ, Bonne G. Laminopathies: a wide spectrum of human diseases. Exp Cell Res. 2007 Jun 10;313 (10):2121–33.
  2. Wydner K, McNeil JA, Lin F, Worman HJ, Lawrence JB. Chromosomal assignment of human nuclear envelope protein genes LMNA, LMNB1, and LBR by fluorescence in situ hybridization. Genomics.1996 Mar 15;32 (3):474–8.
  3. Schreiber KH, Kennedy BK. When lamins go bad: nuclear structure and disease. Cell. 2013 Mar 14;152 (6):1365–75.
  4. Bonne G, Di Barletta MR, Varnous S, Becane HM, Hammouda EH, Merlini L et al. Mutations in the gene encoding lamin A / C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet. 1999 Mar;21 (3):285–8.
  5. Raffaele di Barletta M, Ricci E, Galluzzi G, Tonali P, Mora M, Morandi L et al. Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy. Am J Hum Genet. 2000 Apr;66 (4):1407–12.
  6. Emery AE. Emery-Dreifuss muscular dystrophy – a 40 year retrospective. Neuromuscul Disord. 2000 Jun;10 (4-5):228–32.
  7. Muchir A, Worman HJ. Emery-Dreifuss muscular dystrophy. Curr Neurol Neurosci Rep. 2007 Jan;7 (1):78–83.
  8. Muchir A, Bonne G, van der Kooi AJ, van Meegen M, Baas F, Bolhuis PA et al. 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. 2000 May 22;9 (9):1453–9.
  9. Fatkin D, MacRae C, Sasaki T, Wolff MR, Porcu M, Frenneaux M et al. 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. 1999 Dec 2;341 (23):1715–24.
  10. Bonne G, Mercuri E, Muchir A, Urtizberea A, Becane HM, Recan D et al. Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A / C gene. Ann Neurol. 2000 Aug;48 (2):170–80.
  11. Brodsky GL, Muntoni F, Miocic S, Sinagra G, Sewry C, Mestroni L. Lamin A / C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement. Circulation. 2000 Feb 8;101 (5):473–6.
  12. Quijano-Roy S, Mbieleu B, Bonnemann CG, Jeannet PY, Colomer J, Clarke NF et al. De novo LMNA mutations cause a new form of congenital muscular dystrophy. Ann Neurol. 2008 Aug;64 (2):177–86.
  13. Makri S, Clarke NF, Richard P, Maugenre S, Demay L, Bonne G, Guicheney P. Germinal mosaicism for LMNA mimics autosomal recessive congenital muscular dystrophy. Neuromusc Disord. 2009 Jan;19 (1):26–8.
  14. Mattout A, Pike BL, Towbin BD, Bank EM, Gonzalez-Sandoval A, Stadler MB et al. An EDMD mutation in C elegans lamin blocks muscle-specific gene relocation and compromises muscle integrity. Curr Biol. 2011 Oct 11;21 (19):1603–14.
  15. Dunnigan MG, Cochrane MA, Kelly A, Scott JW. Familial lipoatrophic diabetes with dominant transmission. A new syndrome. Q J Med. 1974 Jan;43 (169):33–48.
  16. Shackleton S, Lloyd DJ, Jackson SN, Evans R, Niermeijer MF, Singh BM et al. LMNA, encoding lamin A / C, is mutated in partial lipodystrophy. Nat Genet. 2000 Feb;24 (2):153–6.
  17. Speckman R, Garg A, Du F, Bennett L, Veile R, Arioglu E et al. 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. 2000 Apr;66 (4):1192–8.
  18. Vigouroux C, Auclair M, Dubosclard E, Pouchelet M, Capeau J, Courvalin JC, Buendia B. Nuclear envelope disorganization in fibroblasts from lipodystrophic patients with heterozygous R482Q / W mutations in the lamin A / C gene. J Cell Sci. 2001 Dec;114 (Pt 24):4459–68.
  19. De Sandre-Giovannoli A, Chaouch M, Kozlov S, Vallat JM, Tazir M, Kassouri N et al. 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. 2002 Mar;70 (3):726–36.
  20. Novelli G, Muchir A, Sangiuolo F, Helbling-Leclerc A, D'Apice MR, Massart C et al. Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A / C. Am J Hum Genet. 2002 Aug;71 (2):426–31.
  21. Agarwal AK, Kazachkova I, Ten S, Garg A. Severe mandibuloacral dysplasia-associated lipodystrophy and progeria in a young girl with a novel homozygous Arg527Cys LMNA mutation. J Clin Endocrinol Metab. 2008 Dec;93 (12):4617–23.
  22. Garg A, Cogulu O, Ozkinay F, Onay H, Agarwal AK. A novel homozygous Ala529Val LMNA mutation in Turkish patients with mandibuloacral dysplasia. J Clin Endocrinol Metab. 2005 Sep;90 (9):5259–64.
  23. Lombardi F, Gullotta F, Columbaro M, Filareto A, D'Adamo M, Vielle A et al. Compound heterozygosity for mutations in LMNA in a patient with a myopathic and lipodystrophic mandibuloacral dysplasia type A phenotype. J Clin Endocrinol Metab. 2007 Nov;92 (11):4467–71.
  24. Hutchinson J. Case of congenital absence of hair, with atrophic condition of the skin and its appendages, in a boy whose mother had been almost wholly bald from alopecia areata from the age of six. Lancet. 1886; I:923.
  25. Gilford H. Ateleiosis and progeria: continuous youth and premature old age. Brit Med J. 1904;2:914–8.
  26. McKusick VA. The clinical observations of Jonathan Hutchinson. Am J Syph Gonorrhea Vener Dis. 1952 Mar;36 (2):101–26.
  27. DeBusk FL. The Hutchinson-Gilford progeria syndrome. J Pediat. 1972 Apr;80 (4):697–724.
  28. Merideth MA, Gordon LB, Clauss S, Sachdev V, Smith AC, Perry MB et al. Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med. 2008 Feb 7;358 (6):592–604.
  29. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003 May 15;423 (6937):293–8.
  30. De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I et al. Lamin A truncation in Hutchinson-Gilford progeria. Science. 2003 Jun 27;300 (5628):2055.
  31. Chen CY, Chi YH, Mutalif RA, Starost MF, Myers TG, Anderson SA et al. Accumulation of the inner nuclear envelope protein Sun1 is pathogenic in progeric and dystrophic laminopathies. Cell. 2012 Apr 27;149 (3):565–77.
  32. Chen L, Lee L, Kudlow BA, Dos Santos HG, Sletvold O, Shafeghati Y et al. LMNA mutations in atypical Werner's syndrome. Lancet. 2003 Aug 9;362 (9382):440–5.
  33. Csoka AB, Cao H, Sammak PJ, Constantinescu D, Schatten GP, Hegele RA. Novel lamin A / C gene (LMNA) mutations in atypical progeroid syndromes. J Med Genet. 2004 Apr;41 (4):304–8.
  34. Verstraeten VL, Broers JL, van Steensel MA, Zinn-Justin S, Ramaekers FC, Steijlen PM et al. Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation. Hum Mol Genet. 2006 Aug 15;15 (16):2509–22.
  35. Funkhouser C, Sknepnek R, Shimi T, Goldman AE, Goldman RD, Olvera de la Cruz M. Mechanical model of blebbing in nuclear lamin meshworks. Proc Natl Acad Sci USA. 2013 Feb 26;110 (9):3248–53.
  36. Shimi T, Pfleghaar K, Kojima S, Pack CG, Solovei I, Goldman AE et al. The A- and B-type nuclear lamin networks: microdomains involved in chromatin organization and transcription. Genes Dev. 2008 Dec 15;22 (24):3409–21.
  37. Crisp M, Liu Q, Roux K, Rattner JB, Shanahan C, Burke B et al. Coupling of the nucleus and cytoplasm: role of the LINC complex. J Cell Biol. 2006 Jan 2;172 (1):41–53.
  38. Malashicheva A, Bogdanova M, Zabirnyk A, Smolina N, Ignatieva E, Freylikhman O et al. Various lamin A / C mutations alter expression profile of mesenchymal stem cells in mutation specific manner. Mol Genet Metab. 2015 Jun-Jul;115 (2-3):118–27.
  39. Mewborn SK, Puckelwartz MJ, Abuisneineh F, Fahrenbach JP, Zhang Y, MacLeod H et al. Altered chromosomal positioning, compaction, and gene expression with a lamin A / C gene mutation. PLoS One. 2010 Dec 14;5 (12):e14342.
  40. Melcer S, Hezroni H, Rand E, Nissim-Rafinia M, Skoultchi A, Stewart CL et al. Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiation. Nat Commun. 2012 Jun 19;3:910.
  41. Rajendran V, Purohit R, Sethumadhavan R. In silico investigation of molecular mechanism of laminopathy caused by a point mutation (R482W) in lamin A / C protein. Amino Acids. 2012 Aug;43 (2):603–15.
  42. Kubben N, Adriaens M, Meuleman W, Voncken JW, van Steensel B, Misteli T. Mapping of lamin A- and progerin-interacting genome regions. Chromosoma. 2012 Oct;121 (5):447–64.
  43. Goldberg MW, Fiserova J, Huttenlauch I, Stick R. A new model for nuclear lamina organization. Biochem Soc Trans. 2008 Dec;36 (Pt 6):1339–43.
  44. Peric-Hupkes D, Meuleman W, Pagie L, Bruggeman SW, Solovei I, Brugman W et al. Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation. Mol Cell. 2010 May 28;38 (4):603–13.
  45. Dechat T, Pfleghaar K, Sengupta K, Shimi T, Shumaker DK, Solimando L, Goldman RD. Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin. Genes Dev. 2008 Apr 1;22 (7):832–53.
  46. Davies BS, Fong LG, Yang SH, Coffinier C, Young SG. The posttranslational processing of prelamin A and disease. Annu Rev Genomics Hum Genet. 2009;10:153–74.
  47. Gonzalez-Suarez I, Redwood AB, Perkins SM, Vermolen B, Lichtensztejin D, Grotsky DA et al. Novel roles for A-type la­mins in telomere biology and the DNA damage response pathway. EMBO J. 2009 Aug 19;28 (16):2414–27.
  48. Attur M, Ben-Artzi A, Yang Q, Al-Mussawir HE, Worman HJ, Abramson SB. Perturbation of nuclear lamin A causes cell death in chondrocytes. Arthritis Rheum. 2012 Jun;64 (6):1940–9.
  49. Bertrand AT, Chikhaoui K, Ben Yaou RB, Bonne G. Clinical and genetic heterogeneity in laminopathies. Biochem Soc Trans. 2011 Dec;39 (6):1687–92.
  50. Kind J, van Steensel B. Genome-nuclear lamina interactions and gene regulation. Curr Opin Cell Biol. 2010 Jun;22 (3):320–5.
  51. Богданова М. А., Гудкова А. Я., Забирник А. С., Игнатьева Е. В., Дмитриева Р. И., Смолина Н. А. и др. Роль ядерных ламинов А / С в остеогенной дифференцировке мультипотентных мезенхимных стромальных клеток. Цитология. 2014;56 (4):260–7 [Bogdanova M. A., Gudkova A. Ya., Zabirnik A. S., Ignat`eva E. V., Dmitrieva R. I., Smolina N. A. i dr. Rol` yaderny`x laminov A / S v osteogennoj differenczirovke mul`tipotentny`x mezenximny`x stromal`ny`x kletok. Czitologiya. 2014;56 (4):260–7].
  52. Малашичева А. Б., Забирник А. С., Смолина Н. А., Омельченко Е. А., Дмитриева Р. И., Костарева А. А. Мутации в гене ламина А / С изменяют дифференцировочный потенциал стромальных клеток жировой ткани. Цитология. 2013;55 (5):313–7 [Malashicheva A. B., Zabirnik A. S., Smolina N. A., Omel`chenko E. A., Dmitrieva R. I., Kostareva A. A. Mutaczii v gene lamina A / S izmenyayut differenczirovochny`j potenczial stromal`ny`x kletok zhirovoj tkani. Czitologiya. 2013;55 (5):313–7].
  53. Burke B, Stewart CL. The nuclear lamins: flexibility in function. Nat Rev Mol Cell Biol. 2013 Jan;14 (1):13–24.
  54. Haas J, Frese KS, Peil B, Kloos W, Keller A, Nietsch R et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J. 2015 May 7;36 (18):1123-35a.
  55. Harakalova M, Kummeling G, Sammani A, Linschoten M, Baas AF, van der Smagt J et al. A systematic analysis of genetic dilated cardiomyopathy reveals numerous ubiquitously expressed and muscle-specific genes. Eur J Heart Fail. 2015 May;17 (5):484–93.
  56. Charron P, Arbustini E, Bonne G. What should the cardiologist to know about lamin disease? Arrhythm Electrophysiol Rev. 2012 Sep;1 (1):22–8.
  57. Liang WC, Yuo CY, Liu CY, Lee CS, Goto K, Hayashi YK, Jong YJ. Novel LMNA mutation in a Taiwanese family with autosomal dominant Emery-Dreifuss muscular dystrophy. J Formos Med Assoc. 2007 Feb;106 (2 Suppl): S27–31.
  58. Hong G, Dan Z, Limeng D, Luxiang C, Bai Y. First report of a novel LMNA mutation in a Chinese family with limb-girdle muscular dystrophy. J Genet. 2014 Dec;93 (3):843–7.
  59. Вайханская Т. Г. Новая система MOGE (S) классификации кардиомиопатий. Медицинские новости. 2014;11:13–9 [Vajxanskaya T. G. Novaya sistema MOGE (S) klassifikaczii kardiomiopatij. Mediczinskie novosti. 2014;11:13–9].
  60. Taylor MR, Fain PR, Sinagra G, Robinson ML, Robertson AD, Carniel E et al. Natural history of dilated cardiomyopathy due to lamin A / C gene mutations. J Am Coll Cardiol. 2003 Mar 5;41 (5):771–80.
  61. Parks SB, Kushner JD, Nauman D, Burgess D, Ludwigsen S, Peterson A et al. Lamin A / C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. Am Heart J. 2008 Jul;156 (1):161–9.
  62. Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM et al. The landscape of genetic variation in dilated cardiomyo­pathy as surveyed by clinical DNA sequencing. Genet Med. 2014 Aug;16 (8):601–8.
  63. Akinrinade O, Ollila L, Vattulainen S, Tallila J, Gentile M, Salmenperä P et al. Genetics and genotype-phenotype correlations in Finnish patients with dilated cardiomyopathy. Eur Heart J. 2015 Sep 7;36 (34):2327–37.
  64. van Berlo JH, de Voogt WG, van der Kooi AJ, van Tintelen JP, Boone G, Yaou RB et al. Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A / C mutations port end a high risk of sudden death? J Mol Med (Berl). 2005 Jan;83 (1):79–83.
  65. Meune C, van Berlo JH, Anselme F, Bonne G, Pinto YM, Duboc D. Primary prevention of sudden death in patients with la­min A / C gene mutations. N Engl J Med. 2006 Jan 12;354 (2):209–10.
  66. Pasotti M, Klersy C, Pilotto A, Marziliano N, Rapezzi C, Serio A et al. Long-term outcome and risk stratification in dilated cardio­laminopathies. J Am Coll Cardiol. 2008 Oct 7;52 (15):1250–60.
  67. Charron P, Arad M, Arbustini E, Basso C, Bilinska Z, Elliott P et al. Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010 Nov;31 (22):2715–26.
  68. van Rijsingen IA, Arbustini E, Elliott PM, Mogensen J, Hermans-van Ast JF, van der Kooi AJ et al. Risk factors for malignant ventri­cular arrhythmias in lamin A / C mutation carriers a European cohort study. J Am Coll Cardiol. 2012 Jan 31;59 (5):493–500.
Vaykhanskaya T. G., Sivitskaya L. N., Danilenko N. G., Kurushko T. V., Davydenko O. G. The multidisciplinary and multisystemic issue of laminopathies: many diseases, one gene. Russian Heart Failure Journal. 2016;17 (3):201–211

To access this material please log in or register

Register Authorize
Ru En