Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart

Program in Biochemistry, Cellular and Molecular Biology, Johns Hopkins School of Medicine, 1830 East Monument Street, Baltimore, MD 21205, USA.
Genome biology (Impact Factor: 10.81). 02/2005; 6(13):R107. DOI: 10.1186/gb-2005-6-13-r107
Source: PubMed


Down syndrome, caused by trisomic chromosome 21, is the leading genetic cause of mental retardation. Recent studies demonstrated that dosage-dependent increases in chromosome 21 gene expression occur in trisomy 21. However, it is unclear whether the entire transcriptome is disrupted, or whether there is a more restricted increase in the expression of those genes assigned to chromosome 21. Also, the statistical significance of differentially expressed genes in human Down syndrome tissues has not been reported.
We measured levels of transcripts in human fetal cerebellum and heart tissues using DNA microarrays and demonstrated a dosage-dependent increase in transcription across different tissue/cell types as a result of trisomy 21. Moreover, by having a larger sample size, combining the data from four different tissue and cell types, and using an ANOVA approach, we identified individual genes with significantly altered expression in trisomy 21, some of which showed this dysregulation in a tissue-specific manner. We validated our microarray data by over 5,600 quantitative real-time PCRs on 28 genes assigned to chromosome 21 and other chromosomes. Gene expression values from chromosome 21, but not from other chromosomes, accurately classified trisomy 21 from euploid samples. Our data also indicated functional groups that might be perturbed in trisomy 21.
In Down syndrome, there is a primary transcriptional effect of disruption of chromosome 21 gene expression, without a pervasive secondary effect on the remaining transcriptome. The identification of dysregulated genes and pathways suggests molecular changes that may underlie the Down syndrome phenotypes.

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    • "It is well known that an extra copy of genes on chromosome 21 is associated with heart malformation. In particular , genes involved in cell adhesion may be associated with heart defects[Barlow et al., 2001;Mao et al., 2005], although this is not well understood. In summary, we report on a patient with a de novo 1.4-Mb deletion at 21q22 presenting with developmental delay. "
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    ABSTRACT: Monosomy 21 is a very rare chromosomal abnormality. At least 45 patients with partial deletion involving 21q11 have been reported. Here, we report a Japanese boy who presented with pre- and postnatal growth delays, psychomotor developmental delay, microcephaly, and iris coloboma. Cytogenetic analysis revealed a de novo 1.4-Mb deletion at 21q22.11 containing 19 protein-coding RefSeq genes. We compared the clinical phenotypes between the present patient and 16 previously reported patients with a deleted region associated with postnatal growth delay and psychomotor developmental delay. Interestingly, ITSN1 was the only gene deleted or disrupted in all cases; this gene is known to be associated with intellectual disability. Microcephaly and brain structural abnormalities including polymicrogyria and agenesis/hypoplasia of the corpus callosum may also result from haploinsufficiency of ITSN1, highlighting its clinical significance for the neurological features of patients with monosomy 21. © 2014 Wiley Periodicals, Inc.
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    • "PCA allows visualization of highly dimensional data along principal component axes. These axes reflect the degree of variance in the data allowing the identification of groups of data having possible biological relevance (Kondo et al., 2013; Mao et al., 2005 "
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    • "Several recent studies based on DNA microarray techniques concluded that an extra or missing chromosome may have a major effect on gene expression on the particular chromosome but only a minor effect on the whole transcriptome [4,8,9,19]. Conversely, some other studies suggested the extra or missing chromosome has a global effect on the whole transcriptome that is regulated by dosage compensation [20,21]. "
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