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Resumen
El síndrome de Hutchinson-Gilford es un síndrome progeroide que se caracteriza por un envejecimiento acelerado que comienza tempranamente en la infancia. El estudio de células de pacientes y el desarrollo de modelos animales (Zmpste24–/–, Zmpste24–/–Lmna+/–, LmnaLCO/LCO que reproducen esta dolencia ha aportado nuevos conocimientos para entender las bases genéticas de esta enfermedad y así también profundizar en las del envejecimiento fisiológico.
El fenotipo característico de este síndrome se debe a alteraciones en la lamina nuclear, estructura formada por un conjunto de filamentos intermedios (laminas A, B y C) que permiten mantener la organización de la envoltura nuclear. Se ha demostrado que una mutación del gen LMNA, que sintetiza la lamina A, es la del depósito de lamina A farnesilada (progerina) que es la causante de las alteraciones en la envoltura nuclear y del fenotipo de este raro síndrome. El empleo de moléculas que actúan sobre diferentes pasos en la síntesis de progerina se está revelando como un futuro terapéutico prometedor para revertir los efectos nocivos de su síntesis.
Palabras clave:
Envoltura nuclear
Laminopatías
Envejecimiento acelerado
Hutchinson-Gilford disease is a progeroid syndrome characterized by accelerated ageing beginning in early childhood. Study of several types of cells from patients with this syndrome and the development of animal models (Zmpste24–/–, Zmpste24–/–Lmna+/–, LmnaLCO/LCO) that mimic this disease have increased knowledge of the genetic foundations of this rare entity and those of normal ageing.
The phenotypic features of this syndrome are caused by alterations in the fibrillar components of the nuclear lamina (lamins A, B, and C), which maintain the structure of the nuclear envelope. A point mutation in the gene for lamin A (LMNA) induces deposit of a farnesylated lamin A (progerin), which causes the nuclear alterations observed in the affected cells. The use of several molecules that interfere with progerin synthesis has been proposed as a promising potential therapeutic approach to reverse the adverse effects of progerin synthesis.
Key words:
Nuclear envelope
Laminopathies
Accelerated ageing
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Bibliografía
[1.]
D. Crespo Santiago.
Biogerontología. Serie Textos Universitarios.
Servicio de Publicaciones de la Universidad de Cantabria, (2006),
[2.]
L. Alonso García, D. Crespo Santiago.
El envejecimiento de los organismos: modelos.
Biogerontología Serie Textos Universitarios, pp. 135-165
[3.]
W.T. Brown.
Genetic diseases of premature aging as models of senescence.
Annu Rev Gerontol Geriatr, 10 (1990), pp. 23-42
[4.]
C.L. Navarro, P. Cau, N. Levy.
Molecular bases of progeroid syndromes.
Hum Mol Genet, 2 (2006), pp. 151-161
[5.]
T. Lindahl, P. Karran, R.D. Wood.
DNA excision repair pathways.
Curr Opin Genet Dev, 7 (1997), pp. 158-169
[6.]
P.K. Sarkar, R.A. Shinton.
Hutchinson-Guilford progeria syndrome.
Postgrad Med J, 77 (2001), pp. 312-317
[7.]
T. Brune, G. Bonne, J. Denecke, N. Elcioglu, R.C. Hennekam, T. Marquardt, et al.
Progeria: a new kind of Laminopathy. Report of the First European Symposium on Progeria and creation of EURO-Progeria, a European Consortium on Progeria and related disorders.
Pediatr Endocrinol Rev, 2 (2004), pp. 39-45
[8.]
J. Cadinanos, I. Varela, C. Lopez-Otin, J.M. Freije.
From immature lamin to premature aging: molecular pathways and therapeutic opportunities.
Cell Cycle, 4 (2005), pp. 1732-1735
[9.]
C. Corso, E.M. Parry, R.G. Faragher, A. Seager, M.H. Green, J.M. Parry.
Molecular cytogenetic insights into the ageing syndrome Hutchinson-Gilford Progeria (HGPS).
Cytogenet Genome Res, 111 (2005), pp. 27-33
[10.]
B.A. Kudlow, B.K. Kennedy.
Aging: progeria and the lamin connection.
Curr Biol, 16 (2006), pp. 652-654
[11.]
H. Lans, J.H. Hoeijmakers.
Cell biology: ageing nucleus gets out of shape.
Nature, 440 (2006), pp. 32-34
[12.]
J. Rankin, S. Ellard.
The laminopathies: a clinical review.
Clin Genet, 70 (2006), pp. 261-274
[13.]
C.L. Ramirez, J. Cadinanos, I. Varela, J.M. Freije, C. Lopez-Otin.
Human progeroid syndromes, aging and cancer: new genetic and epigenetic insights into old questions.
Cell Mol Life Sci, 11 (2006), pp. 1-16
[14.]
J. Hutchinson.
Case of congenital absence of hair, with atropic condition of the skin and its appendages, in a boywhose mother had been almost wholly bald from alopecia areata from the age of six.
Lancet, 1 (1884), pp. 923
[15.]
H. Gilford.
Ateleiosis and progeria: continuous youth and premature old age.
Br Med J, 2 (1904), pp. 914-918
[16.]
A. Del Río Vazquez, F. Carrera Carbo, R. Romero Burgos, C. Salgado Rodríguez, J. Vidal Carreira.
Progeria: report of a case.
Rev Clin Esp, 148 (1978), pp. 315-318
[17.]
R.C. Hennekam.
Hutchinson-Gilford progeria syndrome: review of the phenotype.
Am J Med Genet, 140 (2006), pp. 2603-2624
[18.]
R.L. Pollex, R.A. Hegele.
Hutchinson-Gilford progeria síndrome.
Clin Genet, 66 (2004), pp. 375-381
[19.]
A. Heinrichs.
Ageing: connected clues?.
Nat Rev Mol Cell Biol, 7 (2006), pp. 624
[20.]
L.C. Mounkes, C.L. Stewart.
Aging and nuclear organization: lamins and progeria.
Curr Opin Cell Biol, 16 (2004), pp. 322-327
[21.]
B.C. Capell, F.S. Collins.
Human laminopathies: nuclei gone genetically awry.
Nat Rev Genet, 7 (2006), pp. 940-952
[22.]
M. Eriksson, W.T. Brown, L.B. Gordon, M.W. Glynn, J. Singer, L. Scott, et al.
Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.
Nature, 423 (2003), pp. 293-298
[23.]
C.M. Coffeen, C.E. McKenna, A.H. Koeppen, N.M. Plaster, N. Maragakis, J. Mihalopoulos, et al.
Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31.
Hum Mol Genet, 9 (2000), pp. 787-793
[24.]
M. Giro, J.M. Davidson.
Familial co-segregation of the elastin phenotype in skin fibroblasts from Hutchinson-Gilford progeria.
Mech Ageing Dev, 70 (1993), pp. 63-136
[25.]
Y. Gruenbaum, A. Margalit, R.D. Goldman, D.K. Shumaker, K.L. Wilson.
The nuclear lamina comes of age.
Nat Rev Mol Cell Biol, 1 (2005), pp. 21-31
[26.]
A. Mattout, T. Dechat, S.A. Adam, R.D. Goldman, Y. Gruenbaum.
Nuclear lamins, diseases and aging.
Curr Opin Cell Biol, 18 (2006), pp. 335-341
[27.]
B. Burke, C.L. Stewart.
Life at the edge: the nuclear envelope and human disease.
Nat Rev Mol Cell Biol, 3 (2002), pp. 575-585
[28.]
S.G. Young, M. Meta, S.H. Yang, L.G. Fong.
Prelamin A Farnesylation and Progeroid Syndromes.
J Biol Chem, 281 (2006), pp. 39741-39745
[29.]
Y. Liu, A. Rusinol, M. Sinensky, Y. Wang, Y. Zou.
DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A.
J Cell Sci, 119 (2006), pp. 4644-4649
[30.]
J.A. Ellis.
Emery-Dreifuss muscular dystrophyat the nuclear envelope: 10years on.
Cell Mol Life Sci, 63 (2006), pp. 2702-2709
[31.]
C.J. Reddel, A.S. Weiss.
Lamin A expression levels are unperturbed at the normal and mutant alleles but display partial splice site selection in Hutchinson-Gilford progeria síndrome.
J Med Genet, 41 (2004), pp. 715-717
[32.]
G.K. Leung, W.K. Schmidt, M.O. Bergo, B. Gavino, D.H. Wong, A. Tam, et al.
Biochemical studies of Zmpste24-deficient mice.
J Biol Chem, 276 (2001), pp. 29051-29058
[33.]
M.O. Bergo, B. Gavino, J. Ross, W.K. Schmidt, C. Hong, L.V. Kendall, et al.
Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect.
Proc Natl Acad Sci USA, 99 (2002), pp. 13049-13054
[34.]
L.G. Fong, J.K. Ng, M. Meta, N. Cote, S.H. Yang, C.L. Stewart, et al.
Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice.
Proc Natl Acad Sci USA, 101 (2004), pp. 18111-18116
[35.]
R.D. Goldman, D.K. Shumaker, M.R. Erdos, M. Eriksson, A.E. Goldman, L.B. Gordon, et al.
Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria sindrome.
Proc Natl Acad Sci USA, 101 (2004), pp. 8963-8968
[36.]
L.G. Fong, J.K. Ng, J. Lammerding, T.A. Vickers, M. Meta, N. Cote, et al.
Prelamin A and lamin A appear to be dispensable in the nuclear lamina.
J Clin Invest, 116 (2006), pp. 743-752
[37.]
M. Meta, S.H. Yang, M.O. Bergo, L.G. Fong, S.G. Young.
Protein farnesyltransferase inhibitors and progeria.
Trends Mol Med, 10 (2006), pp. 480-487
[38.]
N. Levy, C. Lopez-Otin, R.C. Hennekam.
Defective prelamin A processing resulting from LMNA or ZMPSTE24 mutations as the cause of restrictive dermopathy.
Arch Dermatol, 141 (2005), pp. 1473-1474
[39.]
S.H. Yang, M. Meta, X. Qiao, D. Frost, J. Bauch, C. Coffinier, et al.
A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation.
J Clin Invest, 116 (2006), pp. 211521
[40.]
B. Liu, J. Wang, K.M. Chan, W.M. Tjia, W. Deng, X. Guan, et al.
Genomic instability in laminopathy-based premature aging.
Nat Med, 11 (2005), pp. 780-785
[41.]
J. Denecke, T. Brune, T. Feldhaus, H. Robenek, C. Kranz, R.J. Auchus, et al.
A homozygous ZMPSTE24 null mutation in combination with a heterozygous mutation in the LMNA gene causes Hutchinson-Gilford progeria syndrome (HGPS): insights into the pathophysiology of HGPS.
Hum Mutat, 27 (2006), pp. 524-531
[42.]
K.N. Dahl, P. Scaffidi, M.F. Islam, A.G. Yodh, K.L. Wilson, T. Misteli.
Distinct structural and mechanical properties of the nuclear lamina in Hutchinson-Gilford progeria syndrome.
Proc Natl Acad Sci USA, 103 (2006), pp. 10271-10276
[43.]
C.V. Wallis, A.N. Sheerin, M.H. Green, C.J. Jones, D. Kipling, R.G. Faragher.
Fibroblast clones from patients with Hutchinson-Gilford progeria can senesce despite the presence of telomerase.
Exp Gerontol, 39 (2004), pp. 461-467
[44.]
C.L. Navarro, A. De Sandre-Giovannoli, R. Bernard, I. Boccaccio, A. Boyer, D. Genevieve, et al.
Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy.
Hum Mol Genet, 13 (2004), pp. 2493-2503
[45.]
P. Scaffidi, L. Gordon, T. Misteli.
The cell nucleus and aging: tantalizing clues and hopeful promises.
PLoS Biol, 11 (2005), pp. 1855-1859
[46.]
P. Scaffidi, T. Misteli.
Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria síndrome.
Nat Med, 11 (2005), pp. 440-445
[47.]
K.J. Kyng, V.A. Bohr.
Gene expression and DNA repair in progeroid syndromes and human Ageing.
Res Rev, 4 (2005), pp. 579-602
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