ABNORMALITAS SELULER DAN MOLEKULER PADA RETT SYNDROME YANG DIPENGARUHI MUTASI GEN MeCP2
Keywords:
Rett Syndrome, MeCP2, Neuron, Mutasi, Gen
Abstract
Rett Syndrome (RTT) adalah gangguan perkembangan neurologis pasca kelahiran yang terkait dengan kromosom X, disebabkan oleh mutasi pada gen yang mengkode methyl-CpG binding protein 2 (MeCP2). MeCP2 berfungsi sebagai regulator transkripsi, baik sebagai penghambat maupun aktivator gen targetnya, sehingga memiliki peran penting dalam menjaga homeostasis fungsi seluler di sistem saraf. Disfungsi MeCP2 mengarah pada berbagai abnormalitas neuropsikiatrik, termasuk gangguan perkembangan, motorik, dan kognitif yang menjadi ciri khas RTT. Berbagai studi menunjukkan bahwa defek pada MeCP2 tidak bersifat permanen, memberikan peluang untuk mengembalikan fungsi normal melalui strategi terapi yang ditargetkan. Intervensi pada tingkat molekuler bertujuan memperbaiki ekspresi gen dan fungsi protein terkait, sehingga meningkatkan fungsi sistem saraf dan kualitas hidup pasien. Artikel ini meninjau mekanisme molekuler yang mendasari RTT, termasuk abnormalitas pada struktur dan fungsi neuron, serta upaya terapi terbaru, seperti penggunaan terapi gen, modulasi epigenetik, dan pendekatan farmakologis untuk memitigasi dampak gangguan MeCP2. Studi-studi ini membuka harapan baru dalam pengembangan terapi personal untuk penderita RTT.
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32. Ausió J. MeCP2 and the enigmatic organization of brain chromatin. Implications for depression and cocaine addiction. Clin Epigenetics. 2016;8:1–13.
33. Nageshappa S, Carromeu C, Trujillo CA, et al. Altered neuronal network and rescue in a human MECP2 duplication model. Mol Psychiatry. 2016;21(2):178–188.
34. Tillotson R, Bird A. The molecular basis of MeCP2 function in the brain. J Mol Biol. 2020;432(6):1602–1623.
35. Li W, Pozzo-Miller L. BDNF deregulation in Rett syndrome. Neuropharmacology. 2014;76:737–746.
36. Cao Q, Zou Q, Zhao X, et al. Regulation of BDNF transcription by Nrf2 and MeCP2 ameliorates MPTP-induced neurotoxicity. Cell Death Discov. 2022;8(1):267.
37. Ehrhart F, Coort SLM, Cirillo E, Smeets E, Evelo CT, Curfs LMG. Rett syndrome–biological pathways leading from MECP2 to disorder phenotypes. Orphanet J Rare Dis. 2016;11:1–13.
38. Maxwell SS. Biochemical characterization of MeCP2 in the brain. Published online 2017.
39. Percy AK, Ananth A, Neul JL. Rett Syndrome: The Emerging Landscape of Treatment Strategies. CNS Drugs. Published online 2024:1–17.
40. Kaufmann WE, Stallworth JL, Everman DB, Skinner SA. Neurobiologically-based treatments in Rett syndrome: opportunities and challenges. Expert Opin orphan drugs. 2016;4(10):1043–1055.
41. Gomathi M, Padmapriya S, Balachandar V. Drug studies on Rett syndrome: from bench to bedside. J Autism Dev Disord. 2020;50(8):2740–2764.
42. Miranda-Lourenço C, Duarte ST, Palminha C, et al. Impairment of adenosinergic system in Rett syndrome: Novel therapeutic target to boost BDNF signalling. Neurobiol Dis. 2020;145:105043.
43. Gadalla KKE, Ross PD, Hector RD, Bahey NG, Bailey MES, Cobb SR. Gene therapy for Rett syndrome: prospects and challenges. Future Neurol. 2015;10(5):467–484.
44. Lim J, Greenspoon D, Hunt A, McAdam L. Rehabilitation interventions in Rett syndrome: a scoping review. Dev Med Child Neurol. 2020;62(8):906–916.
45. Yang D, Robertson HL, Condliffe EG, Carter MT, Dewan T, Gnanakumar V. Rehabilitation therapies in Rett syndrome across the lifespan: A scoping review of human and animal studies. J Pediatr Rehabil Med. 2021;14(1):69–96.
2. Percy AK. Progress in Rett Syndrome: from discovery to clinical trials. Wien Med Wochenschr. 2016;166(11):325.
3. Timpano S, Picketts DJ. Neurodevelopmental disorders caused by defective chromatin remodeling: phenotypic complexity is highlighted by a review of ATRX function. Front Genet. 2020;11:885.
4. Liyanage VRB, Rastegar M. Rett syndrome and MeCP2. Neuromolecular Med. 2014;16:231–264.
5. Yang Y, Kucukkal TG, Li J, Alexov E, Cao W. Binding analysis of methyl-CpG binding domain of MeCP2 and Rett syndrome mutations. ACS Chem Biol. 2016;11(10):2706–2715.
6. Zahorakova D. Rett Syndrome. Chromatin Remodel. Published online 2013.
7. Buchanan CB, Stallworth JL, Scott AE, et al. Behavioral profiles in Rett syndrome: data from the natural history study. Brain Dev. 2019;41(2):123–134.
8. Barnes K V, Coughlin FR, O’Leary HM, et al. Anxiety-like behavior in Rett syndrome: characteristics and assessment by anxiety scales. J Neurodev Disord. 2015;7:1–14.
9. Kyle SM, Vashi N, Justice MJ. Rett syndrome: a neurological disorder with metabolic components. Open Biol. 2018;8(2):170216.
10. Gold WA, Krishnarajy R, Ellaway C, Christodoulou J. Rett syndrome: a genetic update and clinical review focusing on comorbidities. ACS Chem Neurosci. 2018;9(2):167–176.
11. Pitzianti MB, Santamaria Palombo A, Esposito S, Pasini A. Rett syndrome in males: The different clinical course in two brothers with the same microduplication MECP2 Xq28. Int J Environ Res Public Health. 2019;16(17):3075.
12. Brown K, Selfridge J, Lagger S, et al. The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome. Hum Mol Genet. 2016;25(3):558–570.
13. Pidcock FS, Salorio C, Bibat G, et al. Functional outcomes in Rett syndrome. Brain Dev. 2016;38(1):76–81.
14. Frullanti E, Papa FT, Grillo E, et al. Analysis of the phenotypes in the Rett networked database. Int J Genomics. 2019;2019(1):6956934.
15. Xiol C, Vidal S, Pascual-Alonso A, et al. X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients. Sci Rep. 2019;9(1):11983.
16. Kadam SD, Sullivan BJ, Goyal A, Blue ME, Smith-Hicks C. Rett syndrome and CDKL5 deficiency disorder: from bench to clinic. Int J Mol Sci. 2019;20(20):5098.
17. Pascual-Alonso A, Martínez-Monseny AF, Xiol C, Armstrong J. MECP2-related disorders in males. Int J Mol Sci. 2021;22(17):9610.
18. Zhang Q, Zhao Y, Bao X, et al. Familial cases and male cases with MECP2 mutations. Am J Med Genet Part B Neuropsychiatr Genet. 2017;174(4):451–457.
19. Ajithakumari G. Rett Syndrome. TNNMC J Nurs Educ. 2023;11(2):15–18.
20. Takeguchi R, Kuroda M, Tanaka R, et al. Structural and functional changes in the brains of patients with Rett syndrome: A multimodal MRI study. J Neurol Sci. 2022;441:120381.
21. Rodríguez EM. SOCIAL AND SENSORY DEFICITS IN RETT SYNDROME. Published online 2023.
22. Zandl-Lang M, Züllig T, Trötzmüller M, et al. Changes in the cerebrospinal fluid and plasma lipidome in patients with Rett syndrome. Metabolites. 2022;12(4):291.
23. Kong Y, Li Q, Yuan Z, et al. Multimodal neuroimaging in Rett syndrome with MECP2 mutation. Front Neurol. 2022;13:838206.
24. He L, Caudill MS, Jing J, et al. A weakened recurrent circuit in the hippocampus of Rett syndrome mice disrupts long-term memory representations. Neuron. 2022;110(10):1689–1699.
25. Zachariah RM, Rastegar M. Linking epigenetics to human disease and Rett syndrome: the emerging novel and challenging concepts in MeCP2 research. Neural Plast. 2012;2012(1):415825.
26. Du Q, Luu P-L, Stirzaker C, Clark SJ. Methyl-CpG-binding domain proteins: readers of the epigenome. Epigenomics. 2015;7(6):1051–1073.
27. Pejhan S, Rastegar M. Role of DNA methyl-CpG-binding protein MeCP2 in Rett syndrome pathobiology and mechanism of disease. Biomolecules. 2021;11(1):75.
28. Wang J, Xiao Y, Liu C, et al. Emerging physiological and pathological roles of MeCP2 in non-neurological systems. Arch Biochem Biophys. 2021;700:108768.
29. Martínez de Paz A, Ausió J. MeCP2, a modulator of neuronal chromatin organization involved in Rett syndrome. Neuroepigenomics Aging Dis. Published online 2017:3–21.
30. Samaco RC, Neul JL. Complexities of Rett syndrome and MeCP2. J Neurosci. 2011;31(22):7951–7959.
31. Sharma K, Singh J, Frost E, Pillai P. MeCP2 in central nervous system glial cells: current updates. Acta Neurobiol Exp (Wars). 2018;78(1):30–40.
32. Ausió J. MeCP2 and the enigmatic organization of brain chromatin. Implications for depression and cocaine addiction. Clin Epigenetics. 2016;8:1–13.
33. Nageshappa S, Carromeu C, Trujillo CA, et al. Altered neuronal network and rescue in a human MECP2 duplication model. Mol Psychiatry. 2016;21(2):178–188.
34. Tillotson R, Bird A. The molecular basis of MeCP2 function in the brain. J Mol Biol. 2020;432(6):1602–1623.
35. Li W, Pozzo-Miller L. BDNF deregulation in Rett syndrome. Neuropharmacology. 2014;76:737–746.
36. Cao Q, Zou Q, Zhao X, et al. Regulation of BDNF transcription by Nrf2 and MeCP2 ameliorates MPTP-induced neurotoxicity. Cell Death Discov. 2022;8(1):267.
37. Ehrhart F, Coort SLM, Cirillo E, Smeets E, Evelo CT, Curfs LMG. Rett syndrome–biological pathways leading from MECP2 to disorder phenotypes. Orphanet J Rare Dis. 2016;11:1–13.
38. Maxwell SS. Biochemical characterization of MeCP2 in the brain. Published online 2017.
39. Percy AK, Ananth A, Neul JL. Rett Syndrome: The Emerging Landscape of Treatment Strategies. CNS Drugs. Published online 2024:1–17.
40. Kaufmann WE, Stallworth JL, Everman DB, Skinner SA. Neurobiologically-based treatments in Rett syndrome: opportunities and challenges. Expert Opin orphan drugs. 2016;4(10):1043–1055.
41. Gomathi M, Padmapriya S, Balachandar V. Drug studies on Rett syndrome: from bench to bedside. J Autism Dev Disord. 2020;50(8):2740–2764.
42. Miranda-Lourenço C, Duarte ST, Palminha C, et al. Impairment of adenosinergic system in Rett syndrome: Novel therapeutic target to boost BDNF signalling. Neurobiol Dis. 2020;145:105043.
43. Gadalla KKE, Ross PD, Hector RD, Bahey NG, Bailey MES, Cobb SR. Gene therapy for Rett syndrome: prospects and challenges. Future Neurol. 2015;10(5):467–484.
44. Lim J, Greenspoon D, Hunt A, McAdam L. Rehabilitation interventions in Rett syndrome: a scoping review. Dev Med Child Neurol. 2020;62(8):906–916.
45. Yang D, Robertson HL, Condliffe EG, Carter MT, Dewan T, Gnanakumar V. Rehabilitation therapies in Rett syndrome across the lifespan: A scoping review of human and animal studies. J Pediatr Rehabil Med. 2021;14(1):69–96.
Published
2025-01-01
How to Cite
Lestari, I. C., & Suryani Eka Mustika. (2025). ABNORMALITAS SELULER DAN MOLEKULER PADA RETT SYNDROME YANG DIPENGARUHI MUTASI GEN MeCP2. Jurnal Kedokteran STM (Sains Dan Teknologi Medik), 8(1), 45-60. https://doi.org/10.30743/stm.v8i1.763
Section
Tinjauan Pustaka
Copyright (c) 2024 Ira Cinta Lestari, Suryani Eka Mustika
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