5 research outputs found
Molecular signatures of cardiac defects in down syndrome lymphoblastoid cell lines suggest altered ciliome and hedgehog pathways
Forty percent of people with Down syndrome exhibit heart defects, most often an atrioventricular septal defect (AVSD) and less frequently a ventricular septal defect (VSD) or atrial septal defect (ASD). Lymphoblastoid cell lines (LCLs) were established from lymphocytes of individuals with trisomy 21, the chromosomal abnormality causing Down syndrome. Gene expression profiles generated from DNA microarrays of LCLs from individuals without heart defects (CHD-; n = 22) were compared with those of LCLs from patients with cardiac malformations (CHD+; n = 21). After quantile normalization, principal component analysis revealed that AVSD carriers could be distinguished from a combined group of ASD or VSD (ASD+VSD) carriers. From 9,758 expressed genes, we identified 889 and 1,016 genes differentially expressed between CHD- and AVSD and CHD- and ASD+VSD, respectively, with only 119 genes in common. A specific chromosomal enrichment was found in each group of affected genes. Among the differentially expressed genes, more than 65% are expressed in human or mouse fetal heart tissues (GEO dataset). Additional LCLs from new groups of AVSD and ASD+VSD patients were analyzed by quantitative PCR; observed expression ratios were similar to microarray results. Analysis of GO categories revealed enrichment of genes from pathways regulating clathrin-mediated endocytosis in patients with AVSD and of genes involved in semaphorin-plexin-driven cardiogenesis and the formation of cytoplasmic microtubules in patients with ASD-VSD. A pathway-oriented search revealed enrichment in the ciliome for both groups and a specific enrichment in Hedgehog and Jak-stat pathways among ASD+VSD patients. These genes or related pathways are therefore potentially involved in normal cardiogenesis as well as in cardiac malformations observed in individuals with trisomy 21. © 2012 Ripoll et al
Principal component analysis of gene expression profiles of LCLs from individuals with DS and with CHD: red- AVSD (n = 7); green- ASD (n = 8); blue- VSD (n = 6).
<p>Red circle indicates AVSD, blue circle indicates ASD and VSD.</p
Transcriptome signature of heart defects.
<p>Comparison of ratios for DE genes up- or down-regulated in the AVSD or ASD+VSD group between (1) array ratio in the Ts21 CHD<sup>−</sup> vs 2N, (2) array ratio in CHD<sup>+</sup> vs CHD<sup>−</sup>, (3) q-PCR ratio from different experiments in CHD<sup>+</sup> vs CHD<sup>−</sup> using additional samples (total number in parentheses). Gene nomenclature, <i>AUTS2</i>: autism susceptibility candidate 2; <i>CNN2</i>: calponin 2; <i>DSCR3</i>: Down syndrome critical region gene 3; <i>DYNLT3</i>: dynein, light chain, Tctex-type 3; <i>NQO1</i>: NAD(P)H dehydrogenase, quinone 1; <i>OFD1</i>: oral-facial-digital syndrome 1; <i>PDIA4</i>: protein disulfide isomerase family A, member 4; <i>PIGP</i>: phosphatidylinositol glycan anchor biosynthesis, class P; <i>TTC3</i>: tetratricopeptide repeat domain 3; <i>TUBB2B</i>: tubulin, beta 2B; <i>ACTG1</i>: actin, gamma 1; <i>ALDOC</i>: aldolase C, fructose-bisphosphate; <i>CACYBP</i>: calcyclin binding protein; <i>DTYMK</i>: deoxythymidylate kinase (thymidylate kinase); <i>ENO2</i>: enolase 2 (gamma, neuronal); <i>GART</i>: phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase; <i>IFNAR1</i>: interferon (alpha, beta, and omega) receptor 1; <i>PLTP</i>: phospholipid transfer protein; <i>RPL10A</i>: ribosomal protein L10a; <i>TNFAIP2</i>: tumor necrosis factor, alpha-induced protein 2.</p
GO categories in the CDH<sup>+</sup> DE genes.
<p>Analysis of the enrichment of GO categories for the genes DE in the comparison between AVSD or ASD+VSD set of genes and CHD<sup>−</sup> set of genes compared to the genes expressed in LCLs. Analysis used GOrilla software with a p-value threshold at 10<sup>−3</sup>. N - is the total number of genes, B - is the total number of genes associated with a specific null, n - is the number of genes in the group with heart defect, b - is the number of genes in the intersection.</p
Classification of heart defects (CHD+) according to the distribution frequency of their p-values.
<p>Empirical cumulative distributions of p-values for the 2-by-2 Student tests A: AVSD/ASD; B: AVSD/VSD; C: ASD/VSD. Comparisons were obtained for 11 224 tests. The comparison to the uniform distribution shows that there is no overall differential expression between ASD and VSD (less small p-values than for an uniform distribution). Cdf: cumulative distribution function.</p