Results: 2

1.
Figure 1.

Figure 1. From: Concise Review: New Paradigms for Down Syndrome Research Using Induced Pluripotent Stem Cells: Tackling Complex Human Genetic Disease.

HSA21 regions linked to particular Down syndrome (DS) phenotypes. Analysis of human segmental trisomies [13] have identified several dispersed HSA21 regions linked to particular DS phenotypes, including AVSD, AD, IA/DST, MR, HD, and AMKL/TMD. These chromosomal regions are relatively large and overlap incompletely, suggesting the existence of potentially many causative genes in DS (well-known examples indicated at their approximate locations). This is contrary to the long-held notion that genes responsible for DS may be clustered into a single chromosomal region denoted the DSCR [6–11]. The centromere is shown in red, the HSA21 short arm in yellow, and the HSA21 long arm in blue, with light and dark regions reflecting G-banding. Numbers represent distance in Mb from the distal end of the HSA21 short arm. Abbreviations: AD, Alzheimer disease; AMKL/TMD, acute megakaryoblastic leukemia/transient myeloproliferative disorder; AVSD, atrioventricular septal stenosis; DSCR, Down syndrome critical region; HD, Hirschsprung disease; IA/DST, imperforate anus/duodenal stenosis; Mb, megabases; MR, mental retardation; rDNA, recombinant DNA.

James A. Briggs, et al. Stem Cells Transl Med. 2013 March;2(3):175-184.
2.
Figure 2.

Figure 2. From: Concise Review: New Paradigms for Down Syndrome Research Using Induced Pluripotent Stem Cells: Tackling Complex Human Genetic Disease.

Mechanisms underlying etiology and variable expressivity of Down syndrome (DS) phenotypes. Down syndrome phenotypes are classically understood to arise from gene dosage of HSA21 genes (purple arrow), which can be uniquely influenced in different DS individuals by allelic variation or differential imprinting. It is now becoming clear that subsets of HSA21 genes can in fact often deviate significantly from 1.5-fold overexpression [24–29] and that trisomy of HSA21 additionally results in significant genome-wide transcriptome deregulation [29–31], seeming to suggest the existence of additional complex intra- and interchromosomal genetic interactions that may also contribute to DS pathogenesis (blue arrows). Candidate drivers of such mechanisms include HSA21 epigenetic modifiers, transcription factors, or noncoding RNAs. Notably, the complexity of these interactions presents abundant additional opportunities for polymorphism and epistasis to contribute to interindividual differences in gene deregulation in DS, and may be a major driver of variable phenotype expressivity. Gene deregulation in DS underpins a complex etiology that potentially involves multiple cell-autonomous, intercellular and systemic mechanisms, some of which may additionally be influenced by macro- and microenvironmental factors, and that together exert pathological influence at various stages of development or maturity such that normal physiological processes approach a pathological threshold. Abbreviations: miRNA, microRNA; iPSC, induced pluripotent stem cell; lncRNA, long noncoding RNA.

James A. Briggs, et al. Stem Cells Transl Med. 2013 March;2(3):175-184.

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