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Isogenic trisomic-disomic mosaic Down syndrome study design. An individual with mosaicism for trisomy 21 has both trisomic and disomic cells that originated from a single zygote as a constitutional finding. Thus, these trisomic and disomic cells have identical genetic backgrounds (except for the trisomy 21 imbalance) and identical environmental exposures. By measuring trisomic compared to disomic cellular attributes, individual genetic "background" variation is eliminated to allow for direct assessments of trisomy 21-specific influences.
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Down syndrome, which results from a trisomic imbalance for chromosome 21, has been associated with 80+ phenotypic traits. However, the cellular changes that arise in somatic cells due to this aneuploid condition are not fully understood. The primary aim of this study was to determine if germline trisomy 21 is associated with an increase in spontane...
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... approach to tease apart the cellular effects directly attributable to a trisomic imbalance is to study people with mosaicism, since these individuals have both trisomic and disomic (normal) cells that differ only for the presence (or absence) of an additional chromosome [21,22]. Importantly, this "mosaic" study design approach not only removes the confounding effects of inter-individual differences due to total genetic make-up, but also controls for the effects of environmental influences, since the trisomic and disomic cells in people with mosaicism share identical exposure histories (Fig 1). The primary aims of this study were to: (1) determine if there are differences in SCINF between the isogenic trisomic and disomic cells obtained from people with mosaicism for a trisomic imbalance for chromosome 21; and (2) determine if the SCINF in the trisomic and/or disomic cells of people with mosaicism are influenced by age. ...
Citations
... Previously, Bortolai & Melaragno [23] analyzed by SCE one 45,X/46,XX patient in a small study series. The "mosaic" study design approach not only removes the confounding effects of interindividual differences due to total genetic make-up, but also controls for the effects of environmental influences, since both cell lines in individuals with mosaicism share identical exposure histories [24]. ...
... The present study evaluated in vitro selection, PI and SCE frequencies of seventeen mosaic TS patients. So far in the literature, only few studies have evaluated cell proliferation of 45,X cells and of cells having other sex or autosomal chromosome anomalies [12,13,20,24,28,29,[30][31][32]. TS individuals who carry structurally abnormal chromosomes are a unique group, and they have provided opportunities to appraise the cellular consequences of chromosomal imbalance. ...
Turner syndrome (TS) is caused by a complete or partial absence of an X or Y chromosome, including chromosomal mosaicism, affecting 1 in 2,500 female live births. Sister chromatid exchange (SCE) is used as a sensitive indicator of spontaneous chromosome instability. Cells from mosaic patients constitute useful material for SCE evaluations as they grow under the influence of the same genetic background and endogenous and exogenous factors. We evaluated proliferation dynamics and SCE frequencies of 45,X and 46,XN cells of 17 mosaic TS patients. In two participants, 45,X cells exhibited a proliferative disadvantage in relation to 46,XN cells after 72h of cultivation. The analysis of mean PI showed significant differences between 45,X and 46,XN lineages; however there were no intraindividual differences. On the other hand, mean SCE frequencies showed no differences between the two lineages, but there were intraindividual differences in 5 patients. The absence of mean SCE frequency differences between 45,X and 46,XN lineages may indicate that both were equally unstable, as more than 70% of the 46,XN lineages had an anomalous karyotype. However, 46,XN had a higher mean PI, suggesting that the amount of cells with a karyotype distinct from 45,X may increase with time in mosaic TS women.
... Patologías crónico degenerativas: También en este grupo de patologías la frecuencia de micronúcleos es considerablemente alta, entre ella las renales (con y sin terapia de sustitución renal) (75, 76) y las cardiovasculares y metabólicas (obesidad y dislipidemia). Más aún, a largo plazo, los micronúcleos son biomarcador predictivo de mortalidad cardiovascular en sujetos supuestamente sanos, así como de eventos cardiovasculares en enfermedad coronaria conocida (39,(76)(77)(78). ...
La integridad del genoma es esencial para la salud y la continuidad de las especies. Los micronúcleos son biomarcadores de genotoxicidad, y protagonistas de inestabilidad y caos genético. Un micronúcleo o cuerpo de Howell-Jolly, contiene DNA independiente del núcleo, este se origina por retraso anafásico, cuya membrana es inestable y proclive a romperse sin reparación. El DNA contenido en estas estructuras puede condensarse, replicarse, dividirse, no obstante, de manera asincrónica al material genético nuclear, incluso puede sufrir de cromotripisis y reincorporarse al núcleo, lo cual provoca caos genético y con ello cáncer. Por otro lado, si el DNA del micronúcleo es liberado al citosol, desencadena la respuesta inflamatoria crónica, senescencia y apoptosis. Entonces, es vital detectar oportunamente a individuos susceptibles al daño genómico, lo cual permitiría priorizar la atención profiláctica. Por tanto, el objetivo fue hacer una revisión descriptiva sobre algunos de los modelos más empleados e innovadores en la prueba de micronúcleos y los avances celulares y moleculares, en el conocimiento de estas estructuras, así como sus efectos a la salud, para delinear una perspectiva y proponerlos como alternativa preventiva de fácil ejecución en la detección de individuos vulnerables a genotóxicos. Se buscaron artículos en MEDLIANE publicados en los años 2000-2023, que incluían los términos “micronuclei uses and causes” y “micronuclei causes and consecuences”. La inclusión final se determinó después de la revisión de los resúmenes y el posterior análisis del texto completo; se dejaron de incluir artículos una vez que fueron repetitivas las aportaciones.
... These chromosomal aberrations generate many congenital abnormalities such as heart defects, gastrointestinal defects, tracheoesophageal abnormalities, endocrine disorders, vision and hearing disorders, and limb and nervous system anomalies [8][9][10]. Following the complexity of existing comorbidities, numerical chromosomal aberration, such as T13 and T18 are one of the main causes of tions with oxidative stress and mitochondrial dysfunction in their pat Moreover, a growing number of studies have recently demonstrated that formation results from trisomy occurrence [19][20][21][22][23] and was observed to be the T21 phenotype [24][25][26]. T13 and T18 are the most frequently autosom aberrations, excluding T21, where the pathogenesis of this chromosom largely known, and numerous studies have been conducted [5,7,[27][28][29]. changes related to T13 and T18 may also be associated with oxidative portant causative genes being primarily involved in the redox balance re prehensive studies concerning the evaluation of the trisomies' pathomecha plain the development of some malformations and the importance of o which can lead to a better understanding of the effects of the occurrence of [4,30,31]. ...
Autosomal aneuploidies are the most frequently occurring congenital abnormalities and are related to many metabolic disorders, hormonal dysfunctions, neurotransmitter abnormalities, and intellectual disabilities. Trisomies are generated by an error of chromosomal segregation during cell division. Accumulating evidence has shown that deregulated gene expression resulting from the triplication of chromosomes 13 and 18 is associated with many disturbed cellular processes. Moreover, a disturbed oxidative stress status may be implicated in the occurrence of fetal malformations. Therefore, a literature review was undertaken to provide novel insights into the evaluation of trisomy 13 (T13) and 18 (T18) pathogeneses, with a particular concern on the oxidative stress. Corresponding to the limited literature data focused on factors leading to T13 and T18 phenotype occurrence, the importance of oxidative stress evaluation in T13 and T18 could enable the determination of subsequent disturbed metabolic pathways, highlighting the related role of mitochondrial dysfunction or epigenetics. This review illustrates up-to-date T13 and T18 research and discusses the strengths, limitations, and possible directions for future studies. The progressive unification of trisomy-related research protocols might provide potential medical targets in the future along with the implementation of the foundation of modern prenatal medicine.
Chromosome gains are detrimental for the development of the human embryo. As such, autosomal trisomies almost always result in spontaneous abortion, and the rare embryos surviving until live birth suffer from a plethora of pathological defects. There is no treatment currently available to ameliorate the consequences of trisomies, such as Down syndrome (trisomy of chromosome 21). Identifying the source of the phenotypes observed in cells with extra chromosomes is crucial for understanding the underlying molecular causes of trisomy syndromes. Although increased expression of the genes localized on the extra chromosome triggers several pathological phenotypes, an alternative model suggests that global, aneuploidy-associated changes in cellular physiology also contribute to the pathology. Here, we compare the molecular consequences of trisomy syndromes in vivo against engineered cell lines carrying various chromosome gains in vitro. We point out several phenotypes that are shared by variable trisomies and, therefore, might be caused by the presence of an extra chromosome per se, independent of its identity. This alternative view may provide useful insights for understanding Down syndrome pathology and open additional opportunities for diagnostics and treatments.
Mutations of ion channels and G-protein-coupled receptors (GPCRs) are not uncommon and can lead to cardiovascular diseases. Given previously reported multiple factors associated with high mutation rates, we sorted the relative mutability of multiple human genes by (i) proximity to telomeres and/or (ii) high adenine and thymine (A+T) content. We extracted genomic information using the genome data viewer and examined the mutability of 118 ion channel and 143 GPCR genes based on their association with factors (i) and (ii). We then assessed these two factors with 31 genes encoding ion channels or GPCRs that are targeted by the United States Food and Drug Administration (FDA)-approved drugs. Out of the 118 ion channel genes studied, 80 met either factor (i) or (ii), resulting in a 68% match. In contrast, a 78% match was found for the 143 GPCR genes. We also found that the GPCR genes (n = 20) targeted by FDA-approved drugs have a relatively lower mutability than those genes encoding ion channels (n = 11), where targeted genes encoding GPCRs were shorter in length. The result of this study suggests that the use of matching rate analysis on factor-druggable genome is feasible to systematically compare the relative mutability of GPCRs and ion channels. The analysis on chromosomes by two factors identified a unique characteristic of GPCRs, which have a significant relationship between their nucleotide sizes and proximity to telomeres, unlike most genetic loci susceptible to human diseases.
