Análisis de mutaciones en los genes PINK1 Y PARKIN en pacientes colombianos con enfermedad de Parkinson
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Infante Molina, C., Mora Forero, L., Ortega Rojas, J. C., Arboleda-Bustos, C. E., Fernández, W., Arboleda, H., & Arboleda, G. (2014). Análisis de mutaciones en los genes PINK1 Y PARKIN en pacientes colombianos con enfermedad de Parkinson. NOVA, 12(21). https://doi.org/10.22490/24629448.993
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Autores
Carolina Andrea Infante Molina
Laura Marlen Mora Forero
Jenny C. Ortega Rojas
Carlos E. Arboleda-Bustos
William Fernández
Humberto Arboleda
Gonzalo Arboleda
Resumen
La enfermedad de Parkinson es un desorden neurodegenerativo complejo, caracterizado por la pérdida progresiva de las neuronas dopaminérgicas de la sustancia nigra pars compacta. Fac-tores tanto ambientales como genéticos se ha determinado que contribuyen a su desarrollo. Mutaciones en los genes PINK1 y PARKIN han sido asociadas con la enfermedad de inicio temprano e historia familiar. El objetivo del presente estudio fue identificar mutaciones en los genes PINK1 (exones 4 y 6) y PARKIN (exones 2 y 7) en 22 pacientes colombianos con EP de inicio temprano y/o antecedentes familiares, mediante amplificación por PCR y secuen-ciamiento. Las secuencias se compararon con la secuencia consenso de referencia. Se detectó una mutación homocigota de cambio en el marco de lectura ( frameshift) c.155delA en el exón 2 del gen PARKIN en una paciente con inicio temprano de la enfermedad e historia familiar. Además se identificó la presencia de un polimorfismo en el intrón 2 del gen PARKIN en siete pacientes, uno de ellos en estado homocigoto. No se encontraron mutaciones en los exones 4 y 6 del gen PINK1. Se encontró una mutación homocigota c.155delA en el exón 2 de PARKIN de una paciente con la enfermedad de Parkinson de inicio temprano con historia familiar. No se encontraron cambios el gen PINK1.
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Referencias
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2. Qayyum A. Etiology and Pathophysiology of Parkinson’s Di-sease. In: Rana AQ, ed: InTech; 2011.
3. Fahn S, Jankovic J, Hallett M. Chapter 5 - Current concepts on the etiology and pathogenesis of Parkinson disease. Princi-ples and Practice of Movement Disorders 2° Edition ed. Edin-burgh: W.B. Saunders; 2011:93-118.
4. Pradilla AG, Vesga AB, Leon-Sarmiento FE. [National neu-roepidemiological study in Colombia (EPINEURO)]. Rev Panam Salud Publica. 2003;14(2):104-111.
5. Pankratz ND, Wojcieszek J, Foroud T. Parkinson Disease Overview. 2009.
6. Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE. Deciphering the role of heterozygous muta-tions in genes associated with parkinsonism. Lancet Neurol. 2007;6(7):652-662.
7. Camargos ST, Dornas LO, Momeni P, Lees A, Hardy J, Single-ton A, et al. Familial Parkinsonism and early onset Parkinson’s disease in a Brazilian movement disorders clinic: phenotypic characterization and frequency of SNCA, PRKN, PINK1, and LRRK2 mutations. Mov Disord. 2009;24(5):662-666.
8. Scornaienchi V, Civitelli D, De Marco EV, Annesi G, Tarantino P, Rocca FE, et al. Mutation analysis of the PINK1 gene in Southern Italian patients with early- and late-onset parkinso-nism. Parkinsonism Relat Disord. 2012;18(5):651-653.
9. Yonova-Doing E, Atadzhanov M, Quadri M, Kelly P, Shawa N, Musonda ST, et al. Analysis of LRRK2, SNCA, Parkin, PINK1, and DJ-1 in Zambian patients with Parkinson’s disea-se. Parkinsonism Relat Disord. 2012;18(5):567-571.
10. Thomas B, Beal MF. Parkinsons disease. Hum Mol Genet. 2007;16 Spec No. 2:R183-194.
11. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur J Epidemiol. 2011;26 Suppl 1:S1-58.
12. Fung HC, Chen CM, Hardy J, Singleton AB, Lee-Chen GJ, Wu YR. Analysis of the PINK1 gene in a cohort of patients with sporadic early-onset parkinsonism in Taiwan. Neurosci Lett. 2006;394(1):33-36.
13. Cookson MR, Bandmann O. Parkinson’s disease: insights from pathways. Hum Mol Genet. 2010;19(R1):R21-27.
14. Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Mino-shima S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet. 2000;25(3):302-305.
15. Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM. Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci U S A. 2000;97(24):13354-13359.
16. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, et al. PINK1 is selectively stabilized on impaired mitochon-dria to activate Parkin. PLoS Biol. 2010;8(1):e1000298.
17. Douglas J. Diagnostic criteria for Parkinson disease. . Archives of Neurology. 1999; Vol 56(1): 33-39.
18. Clarke CE. Parkinson’s disease. Bmj. 2007;335(7617):441-445.
19. Jankovic J. Parkinsons disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008;79(4):368-376.
20. Sironi F, Primignani P, Zini M, Tunesi S, Ruffmann C, Ricca S, et al. Parkin analysis in early onset Parkinson’s disease. Par-kinsonism Relat Disord. 2008;14(4):326-333.
21. Kitada T, Asakawa S, Hattori N, Matsumine H, Yama-mura Y, Minoshima S, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392(6676):605-608.
22. Periquet M, Latouche M, Lohmann E, Rawal N, De Michele G, Ricard S, et al. Parkin mutations are frequent in patients with isolated early-onset parkinsonism. Brain. 2003;126(Pt 6):1271-1278.
23. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science. 2004;304(5674):1158-1160.
24. Hall TA. BioEdit: a user-friendly biological sequence align-ment editor and analysis program for Windows 95/98/NT. Nucl Acids Symp Ser. 1999;41:95-98.
25. Weckx S, Del-Favero J, Rademakers R, Claes L, Cruts M, De Jonghe P, et al. novoSNP, a novel computational tool for sequen-ce variation discovery. Genome Res. 2005;15(3):436-442.
26. Abbas N, Lucking CB, Ricard S, Durr A, Bonifati V, De Mi-chele G, et al. A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Euro-pe. French Parkinson’s Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson’s Disease. Hum Mol Genet. 1999;8(4):567-574.
27. Munoz E, Tolosa E, Pastor P, Marti MJ, Valldeoriola F, Cam-pdelacreu J, et al. Relative high frequency of the c.255delA parkin gene mutation in Spanish patients with autosomal recessive parkinsonism. J Neurol Neurosurg Psychiatry. 2002;73(5):582-584.
28. Pineda-Trujillo N, Dulcey Cepeda A, Arias Pérez W, More-no 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):122-131.
29. Oliveira SA, Scott WK, Nance MA, Watts RL, Hubble JP, Koller WC, et al. Association study of Parkin gene poly-morphisms with idiopathic Parkinson disease. Arch Neurol. 2003;60(7):975-980.
30. Solla P, Cannas A, Floris G, Murru MR, Corongiu D, Tranquilli S, et al. Parkin Exon Rearrangements and Sequence Variants in LRRK2 Mutations Carriers: Analysis on a Possible Modifier Effect on LRRK2 Penetrance. Parkinsons Dis. 2010;2010:537698.
31. Hoenicka J, Vidal L, Morales B, Ampuero I, Jimenez-Jimenez FJ, Berciano J, et al. Molecular findings in familial Parkinson disease in Spain. Arch Neurol. 2002;59(6):966-970.
32. ras J, Guerreiro R, Ribeiro M, Morgadinho A, Januario C, Dias M, et al. Analysis of Parkinson disease patients from Por-tugal for mutations in SNCA, PRKN, PINK1 and LRRK2. BMC Neurol. 2008;8:1.
33. Dachsel JC, Mata IF, Ross OA, Taylor JP, Lincoln SJ, Hinkle KM, et al. Digenic parkinsonism: investigation of the synergistic effects of PRKN and LRRK2. Neurosci Lett. 2006;410(2):80-84.
34. Rawal N, Periquet M, Lohmann E, Lucking CB, Teive HA, Ambrosio G, et al. New parkin mutations and atypical phe-notypes in families with autosomal recessive parkinsonism. Neurology. 2003;60(8):1378-1381.
35. Okatsu K, Oka T, Iguchi M, Imamura K, Kosako H, Tani N, et al. PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mi-tochondria. Nat Commun. 2012;3:1016.
36. Tan JM, Wong ES, Lim KL.Protein misfolding and ag-gregation in Parkinson’s disease. Antioxid Redox Signal. 2009;11(9):2119-2134.
37. Johnson BN, Berger AK, Cortese GP, Lavoie MJ. The ubi-quitin E3 ligase parkin regulates the proapoptotic function of Bax. Proc Natl Acad Sci U S A. 2012;109(16):6283-6288.
38. Lesage S, Lohmann E, Tison F, Durif F, Durr A, Brice A. Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls. J Med Genet. 2008;45(1):43-46.
39. Hedrich K, Marder K, Harris J, Kann M, Lynch T, Meija-Santana H, et al. Evaluation of 50 probands with early-onset Parkinson’s disease for Parkin mutations. Neurology. 2002;58(8):1239-1246.
40. Brooks J, Ding J, Simon-Sanchez J, Paisan-Ruiz C, Sin-gleton AB, Scholz SW. Parkin and PINK1 mutations in early-onset Parkinson’s disease: comprehensive screening in publicly available cases and control. J Med Genet. 2009;46(6):375-381.
41. Sun M, Latourelle JC, Wooten GF, Lew MF, Klein C, Shill HA, et al. Influence of heterozygosity for parkin mutation on onset age in familial Parkinson disease: the GenePD study. Arch Neurol. 2006;63(6):826-832.
42. |Chung EJ, Ki CS, Lee WY, Kim IS, Kim JY. Clinical features and gene analysis in Korean patients with early-onset Parkin-son disease. Arch Neurol. 2006;63(8):1170-1174.
43. Deng H, Le W, Shahed J, Xie W, Jankovic J. Mutation analysis of the parkin and PINK1 genes in American Cau-casian early-onset Parkinson disease families. Neurosci Lett. 2008;430(1):18-22.
============================================
DOI: http://dx.doi.org/10.22490/24629448.993
2. Qayyum A. Etiology and Pathophysiology of Parkinson’s Di-sease. In: Rana AQ, ed: InTech; 2011.
3. Fahn S, Jankovic J, Hallett M. Chapter 5 - Current concepts on the etiology and pathogenesis of Parkinson disease. Princi-ples and Practice of Movement Disorders 2° Edition ed. Edin-burgh: W.B. Saunders; 2011:93-118.
4. Pradilla AG, Vesga AB, Leon-Sarmiento FE. [National neu-roepidemiological study in Colombia (EPINEURO)]. Rev Panam Salud Publica. 2003;14(2):104-111.
5. Pankratz ND, Wojcieszek J, Foroud T. Parkinson Disease Overview. 2009.
6. Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE. Deciphering the role of heterozygous muta-tions in genes associated with parkinsonism. Lancet Neurol. 2007;6(7):652-662.
7. Camargos ST, Dornas LO, Momeni P, Lees A, Hardy J, Single-ton A, et al. Familial Parkinsonism and early onset Parkinson’s disease in a Brazilian movement disorders clinic: phenotypic characterization and frequency of SNCA, PRKN, PINK1, and LRRK2 mutations. Mov Disord. 2009;24(5):662-666.
8. Scornaienchi V, Civitelli D, De Marco EV, Annesi G, Tarantino P, Rocca FE, et al. Mutation analysis of the PINK1 gene in Southern Italian patients with early- and late-onset parkinso-nism. Parkinsonism Relat Disord. 2012;18(5):651-653.
9. Yonova-Doing E, Atadzhanov M, Quadri M, Kelly P, Shawa N, Musonda ST, et al. Analysis of LRRK2, SNCA, Parkin, PINK1, and DJ-1 in Zambian patients with Parkinson’s disea-se. Parkinsonism Relat Disord. 2012;18(5):567-571.
10. Thomas B, Beal MF. Parkinsons disease. Hum Mol Genet. 2007;16 Spec No. 2:R183-194.
11. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur J Epidemiol. 2011;26 Suppl 1:S1-58.
12. Fung HC, Chen CM, Hardy J, Singleton AB, Lee-Chen GJ, Wu YR. Analysis of the PINK1 gene in a cohort of patients with sporadic early-onset parkinsonism in Taiwan. Neurosci Lett. 2006;394(1):33-36.
13. Cookson MR, Bandmann O. Parkinson’s disease: insights from pathways. Hum Mol Genet. 2010;19(R1):R21-27.
14. Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Mino-shima S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet. 2000;25(3):302-305.
15. Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM. Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci U S A. 2000;97(24):13354-13359.
16. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, et al. PINK1 is selectively stabilized on impaired mitochon-dria to activate Parkin. PLoS Biol. 2010;8(1):e1000298.
17. Douglas J. Diagnostic criteria for Parkinson disease. . Archives of Neurology. 1999; Vol 56(1): 33-39.
18. Clarke CE. Parkinson’s disease. Bmj. 2007;335(7617):441-445.
19. Jankovic J. Parkinsons disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008;79(4):368-376.
20. Sironi F, Primignani P, Zini M, Tunesi S, Ruffmann C, Ricca S, et al. Parkin analysis in early onset Parkinson’s disease. Par-kinsonism Relat Disord. 2008;14(4):326-333.
21. Kitada T, Asakawa S, Hattori N, Matsumine H, Yama-mura Y, Minoshima S, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392(6676):605-608.
22. Periquet M, Latouche M, Lohmann E, Rawal N, De Michele G, Ricard S, et al. Parkin mutations are frequent in patients with isolated early-onset parkinsonism. Brain. 2003;126(Pt 6):1271-1278.
23. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science. 2004;304(5674):1158-1160.
24. Hall TA. BioEdit: a user-friendly biological sequence align-ment editor and analysis program for Windows 95/98/NT. Nucl Acids Symp Ser. 1999;41:95-98.
25. Weckx S, Del-Favero J, Rademakers R, Claes L, Cruts M, De Jonghe P, et al. novoSNP, a novel computational tool for sequen-ce variation discovery. Genome Res. 2005;15(3):436-442.
26. Abbas N, Lucking CB, Ricard S, Durr A, Bonifati V, De Mi-chele G, et al. A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Euro-pe. French Parkinson’s Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson’s Disease. Hum Mol Genet. 1999;8(4):567-574.
27. Munoz E, Tolosa E, Pastor P, Marti MJ, Valldeoriola F, Cam-pdelacreu J, et al. Relative high frequency of the c.255delA parkin gene mutation in Spanish patients with autosomal recessive parkinsonism. J Neurol Neurosurg Psychiatry. 2002;73(5):582-584.
28. Pineda-Trujillo N, Dulcey Cepeda A, Arias Pérez W, More-no 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):122-131.
29. Oliveira SA, Scott WK, Nance MA, Watts RL, Hubble JP, Koller WC, et al. Association study of Parkin gene poly-morphisms with idiopathic Parkinson disease. Arch Neurol. 2003;60(7):975-980.
30. Solla P, Cannas A, Floris G, Murru MR, Corongiu D, Tranquilli S, et al. Parkin Exon Rearrangements and Sequence Variants in LRRK2 Mutations Carriers: Analysis on a Possible Modifier Effect on LRRK2 Penetrance. Parkinsons Dis. 2010;2010:537698.
31. Hoenicka J, Vidal L, Morales B, Ampuero I, Jimenez-Jimenez FJ, Berciano J, et al. Molecular findings in familial Parkinson disease in Spain. Arch Neurol. 2002;59(6):966-970.
32. ras J, Guerreiro R, Ribeiro M, Morgadinho A, Januario C, Dias M, et al. Analysis of Parkinson disease patients from Por-tugal for mutations in SNCA, PRKN, PINK1 and LRRK2. BMC Neurol. 2008;8:1.
33. Dachsel JC, Mata IF, Ross OA, Taylor JP, Lincoln SJ, Hinkle KM, et al. Digenic parkinsonism: investigation of the synergistic effects of PRKN and LRRK2. Neurosci Lett. 2006;410(2):80-84.
34. Rawal N, Periquet M, Lohmann E, Lucking CB, Teive HA, Ambrosio G, et al. New parkin mutations and atypical phe-notypes in families with autosomal recessive parkinsonism. Neurology. 2003;60(8):1378-1381.
35. Okatsu K, Oka T, Iguchi M, Imamura K, Kosako H, Tani N, et al. PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mi-tochondria. Nat Commun. 2012;3:1016.
36. Tan JM, Wong ES, Lim KL.Protein misfolding and ag-gregation in Parkinson’s disease. Antioxid Redox Signal. 2009;11(9):2119-2134.
37. Johnson BN, Berger AK, Cortese GP, Lavoie MJ. The ubi-quitin E3 ligase parkin regulates the proapoptotic function of Bax. Proc Natl Acad Sci U S A. 2012;109(16):6283-6288.
38. Lesage S, Lohmann E, Tison F, Durif F, Durr A, Brice A. Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls. J Med Genet. 2008;45(1):43-46.
39. Hedrich K, Marder K, Harris J, Kann M, Lynch T, Meija-Santana H, et al. Evaluation of 50 probands with early-onset Parkinson’s disease for Parkin mutations. Neurology. 2002;58(8):1239-1246.
40. Brooks J, Ding J, Simon-Sanchez J, Paisan-Ruiz C, Sin-gleton AB, Scholz SW. Parkin and PINK1 mutations in early-onset Parkinson’s disease: comprehensive screening in publicly available cases and control. J Med Genet. 2009;46(6):375-381.
41. Sun M, Latourelle JC, Wooten GF, Lew MF, Klein C, Shill HA, et al. Influence of heterozygosity for parkin mutation on onset age in familial Parkinson disease: the GenePD study. Arch Neurol. 2006;63(6):826-832.
42. |Chung EJ, Ki CS, Lee WY, Kim IS, Kim JY. Clinical features and gene analysis in Korean patients with early-onset Parkin-son disease. Arch Neurol. 2006;63(8):1170-1174.
43. Deng H, Le W, Shahed J, Xie W, Jankovic J. Mutation analysis of the parkin and PINK1 genes in American Cau-casian early-onset Parkinson disease families. Neurosci Lett. 2008;430(1):18-22.
============================================
DOI: http://dx.doi.org/10.22490/24629448.993
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