Identification of altered pathways in Down syndrome-associated congenital heart defects using an individualized pathway aberrance score

Yq, Chen; T, Li; Wy, Guo; Fj, Su; Yx, Zhang

doi:10.4238/gmr.15027601

Cited by 5 publications

(4 citation statements)

References 30 publications

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“…Down syndrome (DS) is the most frequent human chromosomal disorder with a frequency of 1/400 conceptions and 1/1,000 births worldwide (1,2). Since the initial discovery of Lejeune et al (3), it is known that the presence of full or partial chromosome 21 (Hsa21) in three copies (trisomy 21) in the cells of the affected subjects is responsible for the typical features of DS, in particular intellectual disability (ID), cardiovascular defects (4,5) and craniofacial dysmorphism. Importantly, a highly restricted 'Down syndrome critical region' of 34 kb on distal 21q22.13 appears to be specifically duplicated in all individuals with DS (6,7).…”

Section: Introductionmentioning

confidence: 99%

Analysis of a nanoparticle‑enriched fraction of plasma reveals miRNA candidates for Down syndrome pathogenesis

et al. 2019

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Down syndrome (DS) is caused by the presence of part or all of a third copy of chromosome 21. DS is associated with several phenotypes, including intellectual disability, congenital heart disease, childhood leukemia and immune defects. Specific microRNAs (miRNAs/miR) have been described to be associated with DS, although none of them so far have been unequivocally linked to the pathology. The present study focuses to the best of our knowledge for the first time on the miRNAs contained in nanosized RNA carriers circulating in the blood. Fractions enriched in nanosized RNA-carriers were separated from the plasma of young participants with DS and their non-trisomic siblings and miRNAs were extracted. A microarray-based analysis on a small cohort of samples led to the identification of the three most abundant miRNAs, namely miR-16-5p, miR-99b-5p and miR-144-3p. These miRNAs were then profiled for 15 pairs of DS and non-trisomic sibling couples by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results identified a clear differential expression trend of these miRNAs in DS with respect to their non-trisomic siblings and gene ontology analysis pointed to their potential role in a number of typical DS features, including 'nervous system development', 'neuronal cell body' and certain forms of 'leukemia'. Finally, these expression levels were associated with certain typical quantitative and qualitative clinical features of DS. These results contribute to the efforts in defining the DS-associated pathogenic mechanisms and emphasize the importance of properly stratifying the miRNA fluid vehicles in order to probe biomolecules that are otherwise hidden and/or not accessible to (standard) analysis.

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Section: Introductionmentioning

confidence: 99%

Analysis of a nanoparticle‑enriched fraction of plasma reveals miRNA candidates for Down syndrome pathogenesis

et al. 2019

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“…Recently, it was shown that this dual ARD activity is also exhibited by mammalian enzymes (mouse and human ARD isozymes). , In addition to its enzymatic function, several studies have indicated a role of ARD in carcinogenesis and tumor metastasis. ARD is also implicated in hepatitis C infection, Down’s syndrome (DS)-associated congenital heart defects (DS-CHD), and fecundity in Drosophila . In plants, ARD expression is associated with development and fruit ripening and so is of great interest to plant biologists .…”

Section: Introductionmentioning

confidence: 99%

The Metal Drives the Chemistry: Dual Functions of Acireductone Dioxygenase

2017

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Acireductone dioxygenase (ARD) from the methionine salvage pathway (MSP) is a unique enzyme that exhibits dual chemistry determined solely by the identity of the divalent transition metal ion (Fe2+ or Ni2+) in the active site. The Fe2+ containing isozyme catalyzes the on-pathway reaction using substrates 1,2 dihydroxy-3-keto-5-methylthiopent-1-ene (acireductone) and dioxygen to generate formate and the ketoacid precursor of methionine, 2-keto-4-methylthiobutyrate, whereas the Ni2+ containing isozyme catalyzes an off-pathway shunt with the same substrates, generating methylthiopropionate, carbon monoxide and formate. The dual chemistry of ARD was originally discovered in the bacterium Klebsiella oxytoca, but it has recently been shown that mammalian ARD enzymes (mouse and human) are also capable of catalyzing metal-dependent dual chemistry in vitro. This is particularly interesting since carbon monoxide, one of the products of off-pathway reaction, has been identified as an anti-apoptotic molecule in mammals. In addition, several biochemical and genetic studies have indicated an inhibitory role of human ARD in cancer. This comprehensive review describes the biochemical and structural characterization of the ARD family, the proposed experimental and theoretical approaches to establishing mechanisms for the dual chemistry, insights into the mechanism based on comparison with structurally and functionally similar enzymes and the applications of this research to the field of artificial metalloenzymes and synthetic biology.

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“…Recent studies have also suggested the potential contribution of VEGF-A, Sonic Hedgehog (Shh) signaling, the cross-presentation of particulate exogenous antigens (phagosomes) and the methionine salvage pathway, calcineurin/NFAT and folate pathways to the pathogenicity of DS-CHD 11, 15, 31, 51, 59…”

Section: Pathway Signalmentioning

confidence: 99%

“…Using the individualized pathway aberrance score (iPAS) method, Chen YQ et al 59 analyzed 10 human DS patients and 5 control samples and predicted the cross-presentation of particulate exogenous antigens (phagosomes) and the methionine salvage pathway could be good indicators of DS-CHD. However, the specific molecular mechanism needs to be further studied.…”

Section: Pathway Signalmentioning

confidence: 99%

Molecular mechanisms of congenital heart disease in down syndrome

2019

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Down syndrome (DS), as a typical genomic aneuploidy, is a common cause of various birth defects, among which is congenital heart disease (CHD). 40–60% neonates with DS have some kinds of CHD. However, the molecular pathogenic mechanisms of DS associated CHD are still not fully understood. This review summarizes available studies on DS associated CHD from seven aspects so as to provide a crucial and updated overview of what we known so far in this domain.

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Identification of altered pathways in Down syndrome-associated congenital heart defects using an individualized pathway aberrance score

Cited by 5 publications

References 30 publications

Analysis of a nanoparticle‑enriched fraction of plasma reveals miRNA candidates for Down syndrome pathogenesis

Analysis of a nanoparticle‑enriched fraction of plasma reveals miRNA candidates for Down syndrome pathogenesis

The Metal Drives the Chemistry: Dual Functions of Acireductone Dioxygenase

Molecular mechanisms of congenital heart disease in down syndrome

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