Origen parental, estado de no disyunción y recombinación meiótica del cromosoma 21 extra en el síndrome de Down: estudio en una muestra de población colombiana
Palabras clave:
síndrome de Down, no disyunción genética, trisomía, meiosis, recombinación genética, repeticiones de microsatélite
Resumen
Introducción. La trisomía 21 libre es responsable del 95% de los casos de síndrome de Down. La edad materna y la recombinación son los principales factores de riesgo asociados con la concepción de estos individuos. El origen materno de la trisomía ocurre en el 90% de los casos, mientras que los casos de origen paterno y mitótico comparten un 10%. Por otra parte, la recombinación como factor de riesgo para la trisomía 21 no ha sido comprobada completamente.Objetivo. Analizar y validar estas observaciones en una muestra colombiana de casos con trisomía 21 libre.
Materiales y métodos. Se estudiaron 22 afectados con síndrome de Down (trisomía libre) y sus respectivos padres. Se usaron marcadores microsatélites de ADN para determinar el origen en los progenitores, el estado de no disyunción y los eventos de recombinación. Por medio de pruebas no paramétricas se compararon los resultados con los reportados en la literatura. Se realizó análisis de correspondencias múltiples para reconocer los diferentes grupos y sus asociaciones.
Resultados. La distribución de la trisomía 21 fue 90,9% materna, 4,5% paterna y 4,5% mitótica, similar a las reportadas previamente. Sin embargo, existen diferencias en la frecuencia de errores del estado meiótico para origen materno (46,1% meiosis I y 53,9% meiosis II) comparada con la de los reportados previamente (70% meiosis I y 30% meiosis II). El análisis de correspondencias múltiples mostró asociación entre eventos de recombinación local y ausencia de recombinación con estados de no disyunción específicos.
Conclusiones. Las configuraciones quiasmáticas susceptibles están asociadas de manera específica a errores en la meiosis I y la meiosis II materna. Es necesario clasificar la frecuencia de no disyunción en estados meióticos maternos en nuestra población.
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Referencias bibliográficas
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27. Vorsanova SG, Iourov IY, Beresheva AK, Demidova IA, Monakhov VV, Kravets VS et al. Non-disjunction of chromosome 21, alphoid DNA variation, and sociogenetic features of Down syndrome. Tsitol Genet 2005;39:30-6.
28. Brown AS, Feingold E, Broman KW, Sherman SL. Genome-wide variation in recombination in female meiosis: a risk factor for non-disjunction of chromosome 21. Hum Mol Genet 2000;9:515-23.
29. Dej KJ, Ahn C, Orr-Weaver TL. Mutations in the Drosophila condensin subunit dCAP-G: defining the role of condensin for chromosome condensation in mitosis and gene expression in interphase. Genetics 2004;168:895-906.
30. Resnick TD, Satinover DL, Macisaac F, Stukenberg PT, Earnshaw WC, Orr-Weaver TL et al. INCENP and Aurora B Promote Meiotic Sister Chromatid Cohesion through Localization of the Shugoshin MEIS332
in Drosophila. Dev Cell 2006;11:57-68.
31. Martinez-Perez E, Villeneuve AM. HTP-1-dependent constraints coordinate homolog pairing and synapsis and promote chiasma formation during C. elegans meiosis. Genes Dev 2005;19:2727-43.
32. Chikashige Y, Tsutsumi C, Yamane M, Okamasa K, Haraguchi T, Hiraoka Y. Meiotic proteins bqt1 and bqt2 tether telomeres to form the bouquet arrangement of chromosomes. Cell 2006;125:59-69.
33. Yuan L, Liu JG, Hoja MR, Wilbertz J, Nordqvist K, Hoog C. Female germ cell aneuploidy and embryo death in mice lacking the meiosis-specific protein SCP3. Science 2002;296:1115-8.
34. Wang H, Hoog C. Structural damage to meiotic chromosomes impairs DNA recombination and checkpoint control in mammalian oocytes. J Cell Biol 2006;173:485-95.
35. Tease C, Hartshorne GM, Hulten MA. Patterns of meiotic recombination in human fetal oocytes. Am J Hum Genet 2002;70:1469-79.
36. Lenzi ML, Smith J, Snowden T, Kim M, Fishel R, Poulos BK et al. Extreme heterogeneity in the molecular events leading to the establishment of chiasmata during meiosis I in human oocytes. Am J Hum Genet 2005;76:112-27.
37. Cullen CF, Brittle AL, Ito T, Ohkura H. The conserved kinase NHK-1 is essential for mitotic progression and unifying acentrosomal meiotic spindles in Drosophila melanogaster. J Cell Biol 2005;171:593-602.
38. Pearson NJ, Cullen CF, Dzhindzhev NS, Ohkura H. A pre-anaphase role for a Cks/Suc1 in acentrosomal spindle formation of Drosophila female meiosis. EMBO Rep 2006;6:1058-63.
39. Hochwagen A, Tham WH, Brar GA, Amon A. The FK506 binding protein Fpr3 counteracts protein phosphatase 1 to maintainmeiotic recombination checkpoint activity. Cell 2005;122:861-73.
40. Homer HA, McDougall A, Levasseur M, Yallop K, Murdoch AP, Herbert M. Mad2 prevents aneuploidy and premature proteolysis of cyclin B and securin during meiosis I in mouse oocytes. Genes Dev 2005;19:202-7.
41. Warren WD, Gorringe KL. A molecular model for sporadic human aneuploidy. Trends Genet 2006;22:218-24.
2. Center for Disease Control and Prevention. Down syndrome prevalence at birth-United States, 1983- 1990. MMWR Morb Mortal Wkly Rep 1994;43:617-22.
3. Bishop J, Huether CA, Torfs C, Lorey F, Deddens J. Epidemiologic study of Down syndrome in a racially diverse California population, 1989-1991. Am J Epidemiol 1997;145:134-47.
4. Nazer J, Margozzini J, Rodriguez M, Rojas M, Cifuentes L. Disabling malformations in Chile. Latin American Cooperative Study of Congenital Malformations (ECLAMC), 1982-1997. Rev Med Chil
2001;129:67-74.
5. Roizen NJ, Patterson D. Down's syndrome. Lancet 2003;361:1281-9.
6. Ojeda ME, Moreno R. High prevalence of Down syndrome in the Rancagua Hospital in central Chile. Rev Med Chil 2005;133:935-42.
7. Carmichael SL, Shaw GM, Kaidarova Z. Congenital malformations in offspring of Hispanic and African-American women in California, 1989-1997. Birth Defects Res A Clin Mol Teratol 2004;70:382-8.
8. Carothers AD, Hecht CA, Hook EB. International variation in reported livebirth prevalence rates of Down syndrome, adjusted for maternal age. J Med Genet 1999;36:386-93.
9. Carothers AD, Castilla EE, Dutra MG, Hook EB. Search for ethnic, geographic, and other factors in the epidemiology of Down syndrome in South America: analysis of data from the ECLAMC project, 1967-1997. Am J Med Genet 2001;103:149-56.
10. Yunis JJ, Acevedo LE, Campo DS, Yunis EJ. Population data of Y-STR minimal haplotypes in a sample of Caucasian-Mestizo and African descent individuals of Colombia. Forensic Sci Int 2005;151:307-13.
11. Ramírez RE, Isaza C, Gutiérrez MI. La incidencia del síndrome de Down en Cali. Colomb Med 1996;27:138-42.
12. Castilla EE, Lopez-Camelo JS, Campana H. Altitude as a risk factor for congenital anomalies. Am J Med Genet 1999;86:9-14.
13. Savage AR, Petersen MB, Pettay D, Taft L, Allran K, Freeman SB, et al. Elucidating the mechanisms of paternal non-disjunction of chromosome 21 in humans. Hum Mol Genet 1998;7:1221-7.
14. Gomez D, Solsona E, Guitart M, Baena N, Gabau E, Egozcue J et al. Origin of trisomy 21 in Down syndrome cases from a Spanish population registry. Ann Genet 2000;43:23-8.
15. Diego-Alvarez D, Garcia-Hoyos M, Trujillo MJ, Gonzalez-Gonzalez C, Rodriguez de AM, Ayuso C et al. Application of quantitative fluorescent PCR with short tandem repeat markers to the study of
aneuploidies in spontaneous miscarriages. Hum Reprod 2005;20:1235-43.
16. Petersen MB, Mikkelsen M. Nondisjunction in trisomy 21: origin and mechanisms. Cytogenet Cell Genet 2000;91:199-203.
17. Lamb NE, Sherman SL, Hassold TJ. Effect of meiotic recombination on the production of aneuploid gametes in humans. Cytogenet Genome Res 2005;111:250-5.
18. Sherman SL, Freeman SB, Allen EG, Lamb NE. Risk factors for nondisjunction of trisomy 21. Cytogenet Genome Res 2005;111:273-80.
19. Lamb NE, Feingold E, Savage A, Avramopoulos D, Freeman S, Gu Y et al. Characterization of susceptible chiasma configurations that increase the risk for maternal nondisjunction of chromosome 21. Hum Mol Genet 1997;6:1391-9.
20. World Medical Association. World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. JAMA 2000;284:3043-5.
21. Forero DA, Benitez B, Arboleda G, Yunis JJ, Pardo R, Arboleda H. Analysis of functional polymorphisms in three synaptic plasticity-related genes (BDNF, COMT AND UCHL1) in Alzheimer's disease in Colombia. Neurosci Res 2006;55:334-41.
22. Gibbons J, Chakraborty S. Nonparametric Statistical Inference. 3rd. ed. New York: Marcel Dekker; 1992.
23. Ballesta F, Queralt R, Gomez D, Solsona E, Guitart M, Ezquerra M et al. Parental origin and meiotic stage of non-disjunction in 139 cases of trisomy 21. Ann Genet 1999;42:11-5.
24. Warren AC, Chakravarti A, Wong C, Slaugenhaupt SA, Halloran SL, Watkins PC et al. Evidence for reduced recombination on the nondisjoined chromosomes 21 in Down syndrome. Science 1987;237:652-4.
25. Lamb NE, Freeman SB, Savage-Austin A, Pettay D, Taft L, Hersey J et al. Susceptible chiasmate configurations of chromosome 21 predispose to nondisjunction in both maternal meiosis I and meiosis II. Nat Genet 1996;14:400-5.
26. Chen CP, Chern SR, Tsai FJ, Lin CY, Lin YH, Wang W. A comparison of maternal age, sex ratio and associated major anomalies among fetal trisomy 18 cases with different cell division of error. Prenat Diagn 2005;25:327-30.
27. Vorsanova SG, Iourov IY, Beresheva AK, Demidova IA, Monakhov VV, Kravets VS et al. Non-disjunction of chromosome 21, alphoid DNA variation, and sociogenetic features of Down syndrome. Tsitol Genet 2005;39:30-6.
28. Brown AS, Feingold E, Broman KW, Sherman SL. Genome-wide variation in recombination in female meiosis: a risk factor for non-disjunction of chromosome 21. Hum Mol Genet 2000;9:515-23.
29. Dej KJ, Ahn C, Orr-Weaver TL. Mutations in the Drosophila condensin subunit dCAP-G: defining the role of condensin for chromosome condensation in mitosis and gene expression in interphase. Genetics 2004;168:895-906.
30. Resnick TD, Satinover DL, Macisaac F, Stukenberg PT, Earnshaw WC, Orr-Weaver TL et al. INCENP and Aurora B Promote Meiotic Sister Chromatid Cohesion through Localization of the Shugoshin MEIS332
in Drosophila. Dev Cell 2006;11:57-68.
31. Martinez-Perez E, Villeneuve AM. HTP-1-dependent constraints coordinate homolog pairing and synapsis and promote chiasma formation during C. elegans meiosis. Genes Dev 2005;19:2727-43.
32. Chikashige Y, Tsutsumi C, Yamane M, Okamasa K, Haraguchi T, Hiraoka Y. Meiotic proteins bqt1 and bqt2 tether telomeres to form the bouquet arrangement of chromosomes. Cell 2006;125:59-69.
33. Yuan L, Liu JG, Hoja MR, Wilbertz J, Nordqvist K, Hoog C. Female germ cell aneuploidy and embryo death in mice lacking the meiosis-specific protein SCP3. Science 2002;296:1115-8.
34. Wang H, Hoog C. Structural damage to meiotic chromosomes impairs DNA recombination and checkpoint control in mammalian oocytes. J Cell Biol 2006;173:485-95.
35. Tease C, Hartshorne GM, Hulten MA. Patterns of meiotic recombination in human fetal oocytes. Am J Hum Genet 2002;70:1469-79.
36. Lenzi ML, Smith J, Snowden T, Kim M, Fishel R, Poulos BK et al. Extreme heterogeneity in the molecular events leading to the establishment of chiasmata during meiosis I in human oocytes. Am J Hum Genet 2005;76:112-27.
37. Cullen CF, Brittle AL, Ito T, Ohkura H. The conserved kinase NHK-1 is essential for mitotic progression and unifying acentrosomal meiotic spindles in Drosophila melanogaster. J Cell Biol 2005;171:593-602.
38. Pearson NJ, Cullen CF, Dzhindzhev NS, Ohkura H. A pre-anaphase role for a Cks/Suc1 in acentrosomal spindle formation of Drosophila female meiosis. EMBO Rep 2006;6:1058-63.
39. Hochwagen A, Tham WH, Brar GA, Amon A. The FK506 binding protein Fpr3 counteracts protein phosphatase 1 to maintainmeiotic recombination checkpoint activity. Cell 2005;122:861-73.
40. Homer HA, McDougall A, Levasseur M, Yallop K, Murdoch AP, Herbert M. Mad2 prevents aneuploidy and premature proteolysis of cyclin B and securin during meiosis I in mouse oocytes. Genes Dev 2005;19:202-7.
41. Warren WD, Gorringe KL. A molecular model for sporadic human aneuploidy. Trends Genet 2006;22:218-24.
Cómo citar
1.
Ramírez NJ, Belalcázar HM, Yunis JJ, Quintero LN, Arboleda GH, Arboleda H. Origen parental, estado de no disyunción y recombinación meiótica del cromosoma 21 extra en el síndrome de Down: estudio en una muestra de población colombiana. Biomed. [Internet]. 1 de marzo de 2007 [citado 5 de abril de 2025];27(1):141-8. Disponible en: https://revistabiomedicaorg.biteca.online/index.php/biomedica/article/view/240
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2007-03-01
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