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Enfermedad que se origina por alteración durante la MITOSIS

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Abstract

There are many lines of evidence showing that oxidative stress and aberrant mitogenic changes have important roles in the pathogenesis of Alzheimer's disease (AD). However, although both oxidative stress and cell cycle-related abnormalities are early events, occurring before any cytopathology, the relation between these two events, and their role in pathophysiology was, until recently, unclear. However, on the basis of studies of mitogenic and oxidative stress signalling pathways in AD, we proposed a "two-hit hypothesis" which states that although either oxidative stress or abnormalities in mitotic signalling can independently serve as initiators, both processes are necessary to propagate disease pathogenesis. In this paper, we summarise evidence for oxidative stress and abnormal mitotic alterations in AD and explain the two-hit hypothesis by describing how both mechanisms are necessary and invariant features of disease.

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national center for biotechnology information

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Alzheimer's disease: the two-hit hypothesis - PubMed

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There are many lines of evidence showing that oxidative stress and aberrant mitogenic changes have important roles in the pathogenesis of Alzheimer's disease (AD). However, although both oxidative stress and cell cycle-related abnormalities are early events, occurring before any cytopathology, the r ...

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Enfermedad que se origina por alteración durante la MEIOSIS

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. 2021 Mar 22;17(3):e1009462.

doi: 10.1371/journal.pgen.1009462.

Affiliations

¹ Cytogenetics and Genomics Research Unit, Department of Zoology, University of Calcutta, Taraknath Palit Siksha Prangan (Ballygunge Science College Campus), Kolkata, West Bengal, India.

² Department of Zoology, Bangabasi Morning College (affiliated to University of Calcutta), Kolkata, West Bengal, India.

³ Department of Paediatric Medicine, Institute of Post Graduate Medical Education and Research (IPGMER), Bhowanipore, Kolkata, West Bengal, India.

⁴ Department of Paediatric Medicine, Diamond Harbour Government Medical College & Hospital, Diamond Harbour, West Bengal, India.

⁵ Department of Zoology, Bijoykrishna Girls' College (Affiliated to University of Calcutta), Howrah, West Bengal, India.

Free PMC article

Upamanyu Pal et al. PLoS Genet.

Free PMC article

. 2021 Mar 22;17(3):e1009462.

doi: 10.1371/journal.pgen.1009462.

Affiliations

¹ Cytogenetics and Genomics Research Unit, Department of Zoology, University of Calcutta, Taraknath Palit Siksha Prangan (Ballygunge Science College Campus), Kolkata, West Bengal, India.

² Department of Zoology, Bangabasi Morning College (affiliated to University of Calcutta), Kolkata, West Bengal, India.

³ Department of Paediatric Medicine, Institute of Post Graduate Medical Education and Research (IPGMER), Bhowanipore, Kolkata, West Bengal, India.

⁴ Department of Paediatric Medicine, Diamond Harbour Government Medical College & Hospital, Diamond Harbour, West Bengal, India.

⁵ Department of Zoology, Bijoykrishna Girls' College (Affiliated to University of Calcutta), Howrah, West Bengal, India.

Abstract

Altered patterns of recombination on 21q have long been associated with the nondisjunction chromosome 21 within oocytes and the increased risk of having a child with Down syndrome. Unfortunately the genetic etiology of these altered patterns of recombination have yet to be elucidated. We for the first time genotyped the gene MCM9, a candidate gene for recombination regulation and DNA repair in mothers with or without children with Down syndrome. In our approach, we identified the location of recombination on the maternal chromosome 21 using short tandem repeat markers, then stratified our population by the origin of meiotic error and age at conception. We observed that twenty-five out of forty-one single nucleotide polymorphic sites within MCM9 exhibited an association with meiosis I error (N = 700), but not with meiosis II error (N = 125). This association was maternal age-independent. Several variants exhibited aprotective association with MI error, some were neutral. Maternal age stratified characterization of cases revealed that MCM9 risk variants were associated with an increased chance of reduced recombination on 21q within oocytes. The spatial distribution of single observed recombination events revealed no significant change in the location of recombination among women harbouring MCM9 risk, protective, or neutral variant. Additionally, we identified a total of six novel polymorphic variants and two novel alleles that were either risk imparting or protective against meiosis I nondisjunction. In silico analyses using five different programs suggest the risk variants either cause a change in protein function or may alter the splicing pattern of transcripts and disrupt the proportion of different isoforms of MCM9 products within oocytes. These observations bring us a significant step closer to understanding the molecular basis of recombination errors in chromosome 21 nondisjunction within oocytes that leads to birth of child with Down syndrome.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

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References

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Oliver TR, Feingold E, Yu K, Cheung V, Tinker S, Yadav-Shah M, et al.. New insights into human nondisjunction of chromosome 21 in oocytes. PLoS Genet. 2008;4: e1000033. 10.1371/journal.pgen.1000033 - DOI - PMC - PubMed

Sherman SL, Allen EG, Bean LH, Freeman SB. Epidemiology of Down syndrome. Ment Retard Dev Disabil Res Rev. 2007;13: 221-227. 10.1002/mrdd.20157 - DOI - PubMed

Allen EG, Freeman SB, Druschel C, Hobbs CA, O'Leary LA, Romitti PA, et al.. Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects. Hum Genet. 2009;125: 41-52. 10.1007/s00439-008-0603-8 - DOI - PMC - PubMed

Ghosh S, Ghosh P. Genetic Etiology of Chromosome 21 Nondisjunction and Down syndrome Birth: Aberrant Recombination and Beyond. J Down Syndr Chromosom Abnorm. 2015;1. 10.4172/2472-1115.1000102 - DOI

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minichromosome maintenance proteins / genetics*

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national center for biotechnology information

# data[].attributes.attachment_link.title
The etiology of Down syndrome: Maternal MCM9 polymorphisms increase risk of reduced recombination and nondisjunction of chromosome 21 during meiosis I within oocyte - PubMed

# data[].attributes.attachment_link.description
Altered patterns of recombination on 21q have long been associated with the nondisjunction chromosome 21 within oocytes and the increased risk of having a child with Down syndrome. Unfortunately the genetic etiology of these altered patterns of recombination have yet to be elucidated. We for the fir ...

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La citogenética es el estudio de los cromosomas tanto
en número como en estructura.
El cariotipo es la organización de los cromosomas de acuerdo con el tamaño y la posición del centrómero.
El análisis cromosómico requiere de células en metafase, para una mejor clasificación y evaluación de los cromosomas.Las células empleadas para cultivo cromosómico deben ser capaces de crecer y dividirse rápidamente en el cultivo, siendo las más accesibles los leucocito.
Se emplea estimulantes mitóticos como la fitohemaglutinina, cuyo efecto transforma los linfocitos periféricos en células parecidas a blastos capaces de reentrar en el ciclo mitótico.
Una vez se obtienen células en proliferación activa, es
posible detener células en metafase al inhibir la formación del huso acromático mediante el uso de la colchicina. Ayuda a la contracción de los cromosomas, hecho que permite una mejor delineación, un extendido más eficiente y un mejor análisis.
Luego, las células son expuestas a solución salina hipotónica con el fin de asegurar la dispersión adecuada y la observación de los cromosomas dentro de la membrana celular, mediante la extensión en un portaobjetos para posteriormente ser coloreados y analizados al microscopio.

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Es el fenómeno por el cual no se separa alguna de las parejas de cromosomas que vemos en la anafase de la meiosis I para ir cada componente de la pareja a la célula hija correspondiente .
Otras veces se debe al fracaso de separación de las parejas de cromátides en la meiosis II para originar los gametos (óvulos y espermatozoides).
Origina un reparto anómalo de cromosomas: de los 46 originales, 24 irán a un gameto y 22 a otro (en lugar de 23 a cada uno). Tras la fertilización por un gameto normal, se formará un zigoto trisómico o monosómico.
Los errores de segregación cromosómica ocurren con igual frecuencia en meiosis I y meiosis II. Durante la meiosis I los cromosomas homólogos se aparean y forman los bivalentes, cuando ocurre no disyunción, los bivalentes no se separan y ambos homólogos migran hacia el mismo polo. Si hay separación prematura de las cromátidas hermanas, estas se separan y segregan independientemente con distribución inadecuada de una de las cromátidas separadas con el otro homólogo del par cromosómico. Ambos errores en meiosis I originan un gameto heterodisómico. La separación prematura de las cromátidas hermanas, especialmente de los cromosomas pequeños, es el mecanismo más frecuente en el origen de las aneuploidías. Durante la meiosis II se dividen las cromátidas hermanas; en este punto, el error en la segregación provoca que ambas migren hacia el mismo polo, esto origina un gameto isodisómico.