Chromosome 21 and Down syndrome: from genomics to pathophysiology

Antonarakis, Stylianos E.; Lyle, Robert; Dermitzakis, Emmanouil T.; Reymond, Alexandre; Deutsch, Samuel

doi:10.1038/nrg1448

Cited by 611 publications

(533 citation statements)

References 88 publications

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“…An expanding number of studies have reported the presence of chronic oxidative stress and mitochondrial dysfunction in DS at both the cellular and organismal levels (Annerén & Epstein, 1987; Busciglio & Yankner, 1995; Antonarakis et al, 2004; Lott & Dierssen, 2012; Campos et al, 2011). Recently, we reported that decreased mitochondrial activity, increased ROS and mitochondrial fragmentation in DS cells are associated with transcriptional activation of the nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) signaling pathway (Helguera et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Zamponi

Coşkun

et al. 2018

Aging Cell

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SummaryMounting evidence implicates chronic oxidative stress as a critical driver of the aging process. Down syndrome (DS) is characterized by a complex phenotype, including early senescence. DS cells display increased levels of reactive oxygen species (ROS) and mitochondrial structural and metabolic dysfunction, which are counterbalanced by sustained Nrf2‐mediated transcription of cellular antioxidant response elements (ARE). Here, we show that caspase 3/PKCδdependent activation of the Nrf2 pathway in DS and Dp16 (a mouse model of DS) cells is necessary to protect against chronic oxidative damage and to preserve cellular functionality. Mitochondria‐targeted catalase (mCAT) significantly reduced oxidative stress, restored mitochondrial structure and function, normalized replicative and wound healing capacity, and rendered the Nrf2‐mediated antioxidant response dispensable. These results highlight the critical role of Nrf2/ARE in the maintenance of DS cell homeostasis and validate mitochondrial‐specific interventions as a key aspect of antioxidant and antiaging therapies.

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Section: Introductionmentioning

confidence: 99%

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Zamponi

Coşkun

et al. 2018

Aging Cell

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“…Down syndrome (DS) occurs due to non-disjunction of chromosome 21 and is the leading genetic cause of mental retardation (MR) [12,27,33]. Other than the presence of an additional chromosome, factors such as allelic variation in candidate genes for MR may al-so contribute to the complex phenotype.…”

Section: Introductionmentioning

confidence: 99%

A Study of GluK1 Kainate Receptor Polymorphisms in Down Syndrome Reveals Allelic Non-Disjunction at 1173(C/T)

et al. 2009

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Abstract. Mechanisms underlying Down syndrome (DS)-related mental retardation (MR) remain poorly understood. In trisomic offspring, non-disjunction may result in the reduction to homozygosity of a susceptibility allele inherited from a heterozygous parent. Accordingly, we sought evidence for allelic non-disjunction in the GluK1 gene that encodes the critical kainite-binding glutamate receptor subunit-5, maps to chromosome 21q22.1 in the DS critical region and is expressed in brain regions responsible for learning and memory. Three polymorphisms of GluK1 [522(A/C) rs363538; 1173(C/T) rs363430 and 2705(T/C) rs363504] were genotyped in 86 DS patient families by means of PCR-coupled RFLP assays and evaluated with respect to allele frequency, heterozygosity, linkage disequilibrium, stage and parental origin of allelic non-disjunction. We report that the distribution of allele frequencies is in Hardy-Weinberg equilibrium. Moderate heterozygosity (0.339) and a major allele frequency of 0.

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“…In the vast majority of cases, DS results from the presence of an extra copy of chromosome 21. 1,2 A major goal of understanding the molecular pathology of DS is identifying genotype -phenotype correlations, that is the identification of HSA21 genes or other functional genomic elements that contribute to the specific aspects of the phenotype. There have been several general approaches to this problem: (i) mapping of partial trisomy 21 cases in human, 3 -8 (ii) the construction of partial trisomy mouse models with different orthologous regions of HSA21 9 -11 and (iii) the analysis of gene expression in cells and tissues of DS individuals or mouse models of DS, both of the transcriptome 12 -15 and genes from the aneuploid chromosome.…”

Section: Introductionmentioning

confidence: 99%

Genotype–phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21

et al. 2008

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Down syndrome (DS) is one of the most frequent congenital birth defects, and the most common genetic cause of mental retardation. In most cases, DS results from the presence of an extra copy of chromosome 21. DS has a complex phenotype, and a major goal of DS research is to identify genotype -phenotype correlations. Cases of partial trisomy 21 and other HSA21 rearrangements associated with DS features could identify genomic regions associated with specific phenotypes. We have developed a BAC array spanning HSA21q and used array comparative genome hybridization (aCGH) to enable high-resolution mapping of pathogenic partial aneuploidies and unbalanced translocations involving HSA21. We report the identification and mapping of 30 pathogenic chromosomal aberrations of HSA21 consisting of 19 partial trisomies and 11 partial monosomies for different segments of HSA21. The breakpoints have been mapped to within B85 kb. The majority of the breakpoints (26 of 30) for the partial aneuploidies map within a 10-Mb region. Our data argue against a single DS critical region. We identify susceptibility regions for 25 phenotypes for DS and 27 regions for monosomy 21. However, most of these regions are still broad, and more cases are needed to narrow down the phenotypic maps to a reasonable number of candidate genomic elements per phenotype.

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Chromosome 21 and Down syndrome: from genomics to pathophysiology

Cited by 611 publications

References 88 publications

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

A Study of GluK1 Kainate Receptor Polymorphisms in Down Syndrome Reveals Allelic Non-Disjunction at 1173(C/T)

Genotype–phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21

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