Palabras clave
Enfermedad de Parkinson
Mutación
Neuronas
Mutación
Neuronas
Cómo citar
Castañeda-Garzón, S. A., Urrego-Duque, L. F., & Sánchez-Corredor, M. C. (2017). Variantes moleculares en el gen PARK2 en pacientes colombianos con enfermedad de Parkinson. Estudio piloto entre el 2013 y 2014. Médicas UIS, 30(3), 31–8. https://doi.org/10.18273/revmed.v30n3-2017003
Resumen
Introducción: la enfermedad de Parkinson se caracteriza por la degeneración y pérdida de las neuronas dopaminérgicas en el cerebro. Existen factores genéticos involucrados en su desarrollo, en su forma de inicio temprano como el gen PARK2, codificante de la parkina, una E3 ubiquitín ligasa, lo que hace que en caso de mutaciones pierda su capacidad reguladora de degradación de proteínas causando estrés y muerte celular. Objetivo: determinar la presencia de cambios moleculares en los exones 3, 4, y 5 de PARK2 en un grupo de 29 pacientes y 21 controles colombianos con enfermedad de Parkinson de inicio temprano o con antecedentes familiares de ella y la posible correlación con las manifestaciones clínicas de los pacientes. materiales y métodos: estudio descriptivo observacional (entre junio de 2013 y noviembre de 2014) en donde se realizó extracción de ADN de sangre total y se utilizó la técnica de PCR para cada uno de los exones. Finalmente se procedió a la secuenciación automática, análisis de las secuencias con el software Sequencher y comparación con información de bases de datos. Resultados: se identificó una variante en estado homocigoto (Ala46Thr) en el exón 4 en un paciente no reportada anteriormente, posiblemente no patogénica y la variante Ser167Asn en estado heterocigoto en el mismo exón en otro paciente, considerada patogénica y reportada con anterioridad en poblaciones asiática y europea. No se identificaron variantes en los controles. Conclusiones: los cambios no descritos antes en la población colombiana, -Ala46Thr y Ser167Asn-, fueron identificados en el grupo de pacientes. MÉD.UIS. 2017;30(3):31-8.
Referencias
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2. Van der Merwe C, Carr J, Glanzmann B, Bardien S. Exonic rearrangements in the known Parkinson’s disease-causing genes are a rare cause of the disease in South African patients. Neurosci. Lett. 2016;619:168-71.
3. García S, Suárez SS, Dávalo EM, Castillo JL. Perspectiva histórica y aspectos epidemiológicos de la enfermedad de Parkinson. Med Int Mex. 2008;24(1):28-37.
4. Parkinson J. An essay on the shaking palsy. J Neuropsychiatr. Clin. Neurosci. 2002;14(2):223-36.
5. Seirafi M, Kozlov G, Gehring K. Parkin structure and function. FEBS J. 2015;282(11):2076-88.
6. Elizondo-Cárdenas G, Déctor-Carrillo MA, Martínez-Rodríguez HR, Martínez-de Villarreal L, Esmer-Sánchez MC. Genética y la enfermedad de Parkinson: Revisión de actualidades. Med. Univer. 2011;13(51):96-100.
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8. Norris K, Hao R, Chen L, Lai C, Kapur M, Shaughnessy P, et al. Convergence of Parkin, PINK1, and α-Synuclein on Stressinduced Mitochondrial Morphological Remodeling. J. Biol. Chem. 2015;290 (22):13862–74.
9. Huttenlocher J, Stefansson H, Stacy Steinberg, Helgadottir H, Sveinbjörnsdóttir S, Riess O, et al. Heterozygote carriers for CNVs in PARK2 are at increased risk of Parkinson’s disease. Hum. Mol. Genet. 2015; 24(19):5637–43.
10. Bekris LM, Mata IF, Zabetian CP. The Genetics of Parkinson Disease. J. Geriatr. Psychiatry Neurol. 2010;23(4):228–42.
11. Morris HR. Genetics of Parkinson´s disease. Ann. Med. 2005;37:86-96.
12. Ambroziak W, Koziorowski D, Kinga Duszyc K, Skoczylas P, Chromik A, Stawek J, et al. Genomic instability in the PARK2 locus is associated with Parkinson’s disease. J. Appl Genetics. 2015;56(4):51–61.
13. Gómez-Chavarín M, Roldan-Roldan G, Morales-Espinosa R, Pérez-Soto G, Torner-Aguilar C. Mecanismos fisiopatológicos involucrados en la enfermedad de Parkinson. Arch. Neurocien. (Mex. D.F.). 2012;17(1):25-33.
14. Pineda-Trujillo N, Dulcey Cepeda A, Arias Pérez W, Moreno Masmela S, Saldarriaga Henao A, Sepúlveda Falla D, et al. Una mutación en el gen PARK2 causa enfermedad de Parkinson juvenil en una extensa familia colombiana. Iatreia. 2009;22(2):122-31.
15. Peres de Morais S. Juvenile Parkinson disease caused by parkin mutations: large deletions and pathogenic mechanisms. Disertación de maestría. Facultad de Ciencias y Tecnología de la: Universidad Nova de Lisboa. 2011.
16. Biswas A, Maulik M, Das SK, Indian Genome Variation Consortium, Ray K, Ray J. Parkin polymorphisms: risk for Parkinson’s disease in Indian population. Clin. Genet.
2007;72:484-6.
17. Asakawa S, Hattori N, Shimizu A, Shimizu Y, Minoshima S, Mizuno Y, et al. Analysis of eighteen deletion breakpoints in the parkin gene. Biochem. Biophys Res Commun. 2009;389:181-6.
18. De Rijk MC, Tzourio C, Breteler MM, Dartigues JF, Amaducci L, Lopez-Pousa S, et al. Prevalence of parkinsonism and Parkinson’s disease in Europe: the Europarkinson Collaborative Study. European Community Concerted Action on the Epidemiology of Parkinson’s Disease. J Neurol Neurosurg Psychiatry. 1997; 62(1):10-5.
19. West A, Periquet M, Lincoln S, Lücking CB, Nicholl D, Bonifati V, et al. Complex relationship between Parkin mutations and Parkinson disease. Am J Med Genet. 2002;114(5):584-91.
20. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605–8.
21. Sanyal J, Bhaskar LVKS, Chatterjee A, Sarkar B, Chandra Ray B, Raghavendra Rao V. Single Nucleotide Polymorphisms of PARKIN gene in ten indian populations. Antrocom Online J Anthropol. 2011;7(1):135-45.
22. Peng R, Gou Y, Yuan Q, Li T, Latsoudis H, Yuan G, et al. Mutation screening and association analysis of the arkin gene in Parkinson’s disease patients from South-West China. Eur. Neurol. 2003;49(2):85-9.
23. Okubadejo N, Britton A, Crews C, Akinyemi R, Hardy J, Singleton A, et al. Analysis of Nigerians with Apparently Sporadic Parkinson Disease for Mutations in LRRK2, PRKN and ATXN3. Plos One. 2008;3(10)e3421:1-4.
24. Zhang Y, Wang ZZ, Sun HM. Lack of Association Between p.Ser167Asn Variant of Parkin and Parkinson’s Disease: A MetaAnalysis of 15 Studies Involving 2,280 Cases and 2,459 Controls. Am J Med Genet B Neuropsychiatr Genet. 2012;159B(1):38–47.
25. Miller RJ, Wilson SM. Neurological disease: UPS stops delivering! Trends Pharmacol. Sci. 2003;24(1):18-23.
26. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997; 276(5321):2045-7.
27. Gasser T. Genetics of Parkinson’s disease. Clin Genet.1998;54(4):259–65.
28. Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, et al. The ubiquitin pathway in Parkinson’s disease. Nature. 1998;395(6701):451-2.
29. Valente EM, Bentivoglio AR, Dixon PH, Ferraris A, Ialongo T, Frontali M, et al. Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36. Am J Hum Genet. 2001;68(4):895-900.
30. Van Duijn CM, Dekker MC, Bonifati V, Galjaard RJ, HouwingDuistermaat JJ, Snijders PJ, et al. Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. Am J Hum Genet. 2001;69(3):629-34.
31. Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, Van der Brug M, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron. 2004;44(4):595-600.
32. Hicks AA, Pétursson H, Jónsson T, Stefánsson H, Jóhannsdóttir HS, Sainz J, et al. A susceptibility gene for late-onset idiopathic Parkinson’s disease. Ann Neurol. 2002; 52(5):549-55.
33. Pankratz N, Nichols WC, Uniacke SK, Halter C, Murrell J, Rudolph A, et al. Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. Hum Mol Genet. 2003;12:2599–608.
2. Van der Merwe C, Carr J, Glanzmann B, Bardien S. Exonic rearrangements in the known Parkinson’s disease-causing genes are a rare cause of the disease in South African patients. Neurosci. Lett. 2016;619:168-71.
3. García S, Suárez SS, Dávalo EM, Castillo JL. Perspectiva histórica y aspectos epidemiológicos de la enfermedad de Parkinson. Med Int Mex. 2008;24(1):28-37.
4. Parkinson J. An essay on the shaking palsy. J Neuropsychiatr. Clin. Neurosci. 2002;14(2):223-36.
5. Seirafi M, Kozlov G, Gehring K. Parkin structure and function. FEBS J. 2015;282(11):2076-88.
6. Elizondo-Cárdenas G, Déctor-Carrillo MA, Martínez-Rodríguez HR, Martínez-de Villarreal L, Esmer-Sánchez MC. Genética y la enfermedad de Parkinson: Revisión de actualidades. Med. Univer. 2011;13(51):96-100.
7. Darvish H, Movafagh A, Omrani M, Firouzabadi S, Azargashb E, Jamshidi J, et al. Detection of copy number changes in genes associated with Parkinson’s disease in Iranian patients. Neurosci. Lett. 2013;551:75–8.
8. Norris K, Hao R, Chen L, Lai C, Kapur M, Shaughnessy P, et al. Convergence of Parkin, PINK1, and α-Synuclein on Stressinduced Mitochondrial Morphological Remodeling. J. Biol. Chem. 2015;290 (22):13862–74.
9. Huttenlocher J, Stefansson H, Stacy Steinberg, Helgadottir H, Sveinbjörnsdóttir S, Riess O, et al. Heterozygote carriers for CNVs in PARK2 are at increased risk of Parkinson’s disease. Hum. Mol. Genet. 2015; 24(19):5637–43.
10. Bekris LM, Mata IF, Zabetian CP. The Genetics of Parkinson Disease. J. Geriatr. Psychiatry Neurol. 2010;23(4):228–42.
11. Morris HR. Genetics of Parkinson´s disease. Ann. Med. 2005;37:86-96.
12. Ambroziak W, Koziorowski D, Kinga Duszyc K, Skoczylas P, Chromik A, Stawek J, et al. Genomic instability in the PARK2 locus is associated with Parkinson’s disease. J. Appl Genetics. 2015;56(4):51–61.
13. Gómez-Chavarín M, Roldan-Roldan G, Morales-Espinosa R, Pérez-Soto G, Torner-Aguilar C. Mecanismos fisiopatológicos involucrados en la enfermedad de Parkinson. Arch. Neurocien. (Mex. D.F.). 2012;17(1):25-33.
14. Pineda-Trujillo N, Dulcey Cepeda A, Arias Pérez W, Moreno Masmela S, Saldarriaga Henao A, Sepúlveda Falla D, et al. Una mutación en el gen PARK2 causa enfermedad de Parkinson juvenil en una extensa familia colombiana. Iatreia. 2009;22(2):122-31.
15. Peres de Morais S. Juvenile Parkinson disease caused by parkin mutations: large deletions and pathogenic mechanisms. Disertación de maestría. Facultad de Ciencias y Tecnología de la: Universidad Nova de Lisboa. 2011.
16. Biswas A, Maulik M, Das SK, Indian Genome Variation Consortium, Ray K, Ray J. Parkin polymorphisms: risk for Parkinson’s disease in Indian population. Clin. Genet.
2007;72:484-6.
17. Asakawa S, Hattori N, Shimizu A, Shimizu Y, Minoshima S, Mizuno Y, et al. Analysis of eighteen deletion breakpoints in the parkin gene. Biochem. Biophys Res Commun. 2009;389:181-6.
18. De Rijk MC, Tzourio C, Breteler MM, Dartigues JF, Amaducci L, Lopez-Pousa S, et al. Prevalence of parkinsonism and Parkinson’s disease in Europe: the Europarkinson Collaborative Study. European Community Concerted Action on the Epidemiology of Parkinson’s Disease. J Neurol Neurosurg Psychiatry. 1997; 62(1):10-5.
19. West A, Periquet M, Lincoln S, Lücking CB, Nicholl D, Bonifati V, et al. Complex relationship between Parkin mutations and Parkinson disease. Am J Med Genet. 2002;114(5):584-91.
20. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605–8.
21. Sanyal J, Bhaskar LVKS, Chatterjee A, Sarkar B, Chandra Ray B, Raghavendra Rao V. Single Nucleotide Polymorphisms of PARKIN gene in ten indian populations. Antrocom Online J Anthropol. 2011;7(1):135-45.
22. Peng R, Gou Y, Yuan Q, Li T, Latsoudis H, Yuan G, et al. Mutation screening and association analysis of the arkin gene in Parkinson’s disease patients from South-West China. Eur. Neurol. 2003;49(2):85-9.
23. Okubadejo N, Britton A, Crews C, Akinyemi R, Hardy J, Singleton A, et al. Analysis of Nigerians with Apparently Sporadic Parkinson Disease for Mutations in LRRK2, PRKN and ATXN3. Plos One. 2008;3(10)e3421:1-4.
24. Zhang Y, Wang ZZ, Sun HM. Lack of Association Between p.Ser167Asn Variant of Parkin and Parkinson’s Disease: A MetaAnalysis of 15 Studies Involving 2,280 Cases and 2,459 Controls. Am J Med Genet B Neuropsychiatr Genet. 2012;159B(1):38–47.
25. Miller RJ, Wilson SM. Neurological disease: UPS stops delivering! Trends Pharmacol. Sci. 2003;24(1):18-23.
26. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997; 276(5321):2045-7.
27. Gasser T. Genetics of Parkinson’s disease. Clin Genet.1998;54(4):259–65.
28. Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, et al. The ubiquitin pathway in Parkinson’s disease. Nature. 1998;395(6701):451-2.
29. Valente EM, Bentivoglio AR, Dixon PH, Ferraris A, Ialongo T, Frontali M, et al. Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36. Am J Hum Genet. 2001;68(4):895-900.
30. Van Duijn CM, Dekker MC, Bonifati V, Galjaard RJ, HouwingDuistermaat JJ, Snijders PJ, et al. Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. Am J Hum Genet. 2001;69(3):629-34.
31. Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, Van der Brug M, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron. 2004;44(4):595-600.
32. Hicks AA, Pétursson H, Jónsson T, Stefánsson H, Jóhannsdóttir HS, Sainz J, et al. A susceptibility gene for late-onset idiopathic Parkinson’s disease. Ann Neurol. 2002; 52(5):549-55.
33. Pankratz N, Nichols WC, Uniacke SK, Halter C, Murrell J, Rudolph A, et al. Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. Hum Mol Genet. 2003;12:2599–608.
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