Progeria de Hutchinson-Gilford como uma Janela para o Envelhecimento Humano: Perspectivas Genéticas, Celulares e Terapêuticas
Barra lateral de artigos
Como Citar
Este trabalho está licenciado sob uma licença Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
##plugins.themes.bootstrap3.displayStats.downloads##
Societal impact
Conteúdo do artigo principal
Resumo
A síndrome de progeria de Hutchinson-Gilford (HGPS) é uma doença genética rara e devastadora caracterizada por envelhecimento precoce. Essa doença é causada por uma mutação autossômica dominante no gene LMNA, que produz a proteína progerina defeituosa, responsável pelas alterações celulares que induzem o envelhecimento acelerado. Os primeiros sinais de HGPS geralmente aparecem entre 6 e 12 meses de idade, com manifestações clínicas como retardo do crescimento, perda de gordura corporal, alopecia e anormalidades ósseas. À medida que a doença progride, desenvolvem-se problemas cardiovasculares graves, principalmente aterosclerose e fibrose, levando à morte por insuficiência cardíaca ou infarto do miocárdio em uma idade média de 14,5 anos. O diagnóstico é confirmado pelo sequenciamento genético para a mutação c.1824C>T no gene LMNA. Embora não haja cura, o inibidor da farnesilação Lonafarnib demonstrou melhorar a qualidade de vida e prolongar a sobrevida. O estudo da HGPS proporciona uma perspectiva única para a compreensão do envelhecimento, uma vez que compartilha mecanismos moleculares com a senescência natural, como disfunção mitocondrial e estresse oxidativo. A pesquisa em HGPS não apenas aprofunda nossa compreensão dessa doença, mas também abre novas vias terapêuticas potenciais para condições relacionadas à idade.
Detalhes do artigo
Referências
1. National Human Genome Research Institute. Progeria [Internet]. [consultado el 9 de noviembre de 2024]. Disponible en: https://www.genome.gov/es/genetics-glossary/Progeria
2. Cisneros B, García-Aguirre I, De Ita M, Arrieta-Cruz I, Rosas-Vargas H. Hutchinson-Gilford progeria syndrome: cellular mechanisms and therapeutic perspectives. Arch Med Res. 2023;54(5):102837.
3. Zambrano RM, Baquero Rodríguez R, Martínez Ariza L. Síndrome de progeria de Hutchinson-Gilford como causa de talla baja. An Pediatr (Engl Ed). 2009;71(3):273-275.
4. Bar DZ, Arlt MF, Brazier JF. A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome. J Med Genet. 2017;54(3):212-216.
5. Gordon LB. The premature aging syndrome: Hutchinson-Gilford progeria syndrome—insights into normal aging. En: Brocklehurst’s textbook of geriatric medicine and gerontology. 8ª ed. Elsevier; 2017. p. 53-60.
6. Gordon LB, Brown WT, Collins FS. Hutchinson-Gilford Progeria Syndrome. 2003 Dec 12 [Updated 2025 Mar 13]. En: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.
7. Dulcey Sarmiento LA, Parra Rincón CA, Wadnipar Gutierrez AL. Progeria y su asociación con enfermedad cerebrovascular: primer reporte de un caso en la literatura nacional de Colombia. Ciencia Latina Rev Cient Multidiscip. 2023;7(5):6565-6574.
8. Díez-Díez M, Amorós-Pérez M, de la Barrera J. Clonal hematopoiesis is not prevalent in Hutchinson-Gilford progeria syndrome. Geroscience. 2023;45(2):1231-1236.
9. The Progeria Research Foundation. El manual sobre progeria: una guía para familias y proveedores de atención médica de niños con progeria. Gordon LB, editor. Estados Unidos: The Progeria Research Foundation; 2010.
10. Gordon LB, Rothman FG, López-Otín C, Misteli T. Progeria: a paradigm for translational medicine. Cell. 2014;156(3):400-407.
11. Gordon LB, Massaro J, D’Agostino RB, et al. Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome. Circulation. 2014;130(1):27-34.
12. DuBose AJ, Lichtenstein ST, Petrash NM, Erdos MR, Gordon LB, Collins FS. Everolimus rescues multiple cellular defects in laminopathy-patient fibroblasts. Proc Natl Acad Sci U S A. 2018;115(16):4206-4211.
13. Arenas Sordo M de la L, Hernández Zamora E, Montoya Pérez LA, Aldape Barrios BC. Síndrome de Cockayne: informe de un caso. Revisión de la literatura. Med Oral Patol Oral Cir Bucal. 2006;11(3): E236-8.
14. Wambach JA, Wegner DJ, Patni N. Bi-allelic POLR3A loss-of-function variants cause autosomal-recessive Wiedemann-Rautenstrauch syndrome. Am J Hum Genet. 2018;103(6):968-975.
15. The Progeria Research Foundation. PRF by the numbers [Internet]. 2024 [consultado el 6 de noviembre de 2024]. Disponible en: https://www.progeriaresearch.org/prf-by-the-numbers/
16. Gordon LB, Shappell H, Massaro J, et al. Association of lonafarnib treatment vs no treatment with mortality rate in patients with Hutchinson-Gilford progeria syndrome. JAMA. 2018;319(16):1687-1695.
17. Instituto Nacional de Salud (Colombia). Informe del evento de enfermedades huérfanas-raras, Colombia 2018 [Internet]. Bogotá: INS; 2019 [consultado el 9 de noviembre de 2024]. Disponible en: https://www.ins.gov.co/buscador-eventos/Informesdeevento/ENFERMEDADES%20HU%C3%89RFANAS-RARAS_2019.pdf
18. Pachajoa H, Claros-Hulbert A, García-Quintero X, Perafan L, Ramírez A, Zea-Vera AF. Hutchinson-Gilford progeria syndrome: clinical and molecular characterization. Appl Clin Genet. 2020;13:159-164.
19. Dittmer TA, Misteli T. The lamin protein family. Genome Biol. 2011;12(5):222.
20. National Center for Biotechnology Information (NCBI). LMNA lamin A/C [Internet]. [consultado el 6 de noviembre de 2024]. Disponible en: https://www.ncbi.nlm.nih.gov/gtr/genes/4000/
21. Gruenbaum Y, Goldman RD, Meyuhas R. The nuclear lamina and its functions in the nucleus. In: International Review of Cytology. Vol. 226. San Diego: Academic Press; 2003. p. 1-62.
22. Meta M, Yang SH, Bergo MO, Fong LG, Young SG. Protein farnesyltransferase inhibitors and progeria. Trends Mol Med. 2006;12(10):480-487.
23. Noda A, Mishima S, Hirai Y, et al. Progerin, the protein responsible for the Hutchinson-Gilford progeria syndrome, increases the unrepaired DNA damages following exposure to ionizing radiation. Genes Environ. 2015;37:13.
24. De Sandre-Giovannoli A, Bernard R, Cau P. Lamin A truncation in Hutchinson-Gilford progeria. Science. 2003;300(5628):2055.
25. Casey PJ, Seabra MC. Protein prenyltransferases. J Biol Chem. 1996;271(10):5289-5292.
26. Gao J, Liao J, Yang GY. CAAX-box protein, prenylation process and carcinogenesis. Am J Transl Res. 2009;1(3):312-325.
27. Palsuledesai CC, Distefano MD. Protein prenylation: enzymes, therapeutics, and biotechnology applications. ACS Chem Biol. 2015;10(1):51-62.
28. Casasola A, Scalzo D, Nandakumar V. Prelamin A processing, accumulation and distribution in normal cells and laminopathy disorders. Nucleus. 2016;7(1):84-102.
29. Goldman RD, Shumaker DK, Erdos MR, et al. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2004;101(24):8963-8968.
30. Chaudhary MK, Singh S, Rizvi SI. Redox imbalance in a model of rat mimicking Hutchinson-Gilford progeria syndrome. Biochem Biophys Res Commun. 2017;491(2):361-367.
31. Dreesen O. Towards delineating the chain of events that cause premature senescence in the accelerated aging syndrome Hutchinson–Gilford progeria (HGPS). Biochem Soc Trans. 2020;48(3):981-991.
32. González Morán MG. Síndrome de Progeria de Hutchinson-Gilford. Causas, investigación y tratamientos farmacológicos. Educaciónquímica. 2014;24(4):432-439.
33. Sinclair DA, LaPlante MD. Lifespan: why we age and why we don't have to. Nueva York: Atria Books; 2019.
34. Trigueros-Motos L. Hutchinson-Gilford progeria syndrome, cardiovascular disease and oxidative stress. Front Biosci (Schol Ed). 2011;S3(1):1285.
35. Olive M, Harten I, Mitchell R. Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of aging. Arterioscler Thromb Vasc Biol. 2010;30(11):2301-2309.
36. Rivera-Torres J, Calvo CJ, Llach A. Cardiac electrical defects in progeroid mice and Hutchinson-Gilford progeria syndrome patients with nuclear lamina alterations. Proc Natl Acad Sci U S A. 2016;113(46):E7250-E7259.
37. Ragnauth CD, Warren DT, Liu Y. Prelamin A acts to accelerate smooth muscle cell senescence and is a novel biomarker of human vascular aging. Circulation. 2010;121(20):2200-2210.
38. Hennekam RCM. Hutchinson–Gilford progeria syndrome: review of the phenotype. Am J Med Genet A. 2006;140A(23):2603-2624.
39. Gordon CM, Gordon LB, Snyder BD, et al. Hutchinson-Gilford progeria is a skeletal dysplasia. J Bone Miner Res. 2011;26(7):1670-1679.
40. Cleveland RH, Gordon LB, Kleinman ME, et al. A prospective study of radiographic manifestations in Hutchinson-Gilford progeria syndrome. Pediatr Radiol. 2012;42(9):1089-1098.
41. Ullrich NJ, Gordon LB. Hutchinson–Gilford progeria syndrome. In: Martini L, ed. Handbook of Clinical Neurology. Vol. 132. Pediatric Neurology Part I. Ámsterdam: Elsevier; 2015:249-264.
42. Xu S, Jin ZG. Hutchinson–Gilford progeria syndrome: cardiovascular pathologies and potential therapies. Trends Biochem Sci. 2019;44(7):561-564.
43. Lian J, Du L, Li Y. Hutchinson-Gilford progeria syndrome: cardiovascular manifestations and treatment. Mech Ageing Dev. 2023;216:111879.
44. Silvera VM, Gordon LB, Orbach DB, Campbell SE, Machan JT, Ullrich NJ. Imaging characteristics of cerebrovascular arteriopathy and stroke in Hutchinson-Gilford progeria syndrome. Am J Neuroradiol. 2013;34(5):1091-1097.
45. Scaffidi P, Gordon L, Misteli T. The cell nucleus and aging: Tantalizing clues and hopeful promises. PLoS Biology Vol. 3/11/2005, e395.
46. Online Mendelian Inheritance in Man (OMIM). LMNA: variantes alélicas. Johns Hopkins University; 2024. Disponible en: https://www.omim.org/allelicVariants/150330
47. Delgado-Luengo WN, Petty EM, Solís-Añez E. Petty–Laxova–Wiedemann progeroid syndrome: further phenotypical delineation and confirmation of a rare syndrome of premature aging. Am J Med Genet A. 2009;149A(10):2200-2205.
48. Laugel V. Cockayne Syndrome. 2000 Dec 28 [Updated 2024 Aug 29]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Disponible en: https://www.ncbi.nlm.nih.gov/books/NBK1342/
49. Gordon LB, Kleinman ME, Miller DT. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2012;109(41):16666-16671.
50. Kieran MW, Gordon L, Kleinman M. New approaches to progeria. Pediatrics. 2007;120(4):834-841.
51. Chen X, Yao H, Andrés V, Bergo MO, Kashif M. Status of treatment strategies for Hutchinson–Gilford progeria syndrome with a focus on prelamin: a posttranslational modification. Basic Clin Pharmacol Toxicol. 2022;131(4):217-223.
52. Gonzalez JM. A-type lamins and Hutchinson-Gilford progeria syndrome: pathogenesis and therapy. Front Biosci (Schol Ed). 2011;S3(1):1133.
53. Gordon LB, MacDonnell L. Physical therapy and occupational therapy in progeria [Internet]. Peabody (MA): The Progeria Research Foundation; 2004 [citado 1 jul 2025]. Disponible en: http://www.progeriaresearch.org/assets/files/pdf/Physical%20Therapy%2807-04%29.pdf