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...
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2012
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oai:doaj.org-article:61fc4e0889fa44edbfb11babca0036532021-11-18T07:09:15ZMolecular signatures of cardiac defects in Down syndrome lymphoblastoid cell lines suggest altered ciliome and Hedgehog pathways.1932-620310.1371/journal.pone.0041616https://doaj.org/article/61fc4e0889fa44edbfb11babca0036532012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22912673/?tool=EBIhttps://doaj.org/toc/1932-6203Forty 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.Clémentine RipollIsabelle RivalsEmilie Ait Yahya-GraisonLuce DauphinotEvelyne PalyClothilde MircherAimé RavelYann GrattauHenri BléhautAndré MégarbaneGuy DembourBénédicte de FréminvilleRenaud TouraineNicole CréauMarie Claude PotierJean Maurice DelabarPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 8, p e41616 (2012) |
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Medicine R Science Q |
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Medicine R Science Q Clémentine Ripoll Isabelle Rivals Emilie Ait Yahya-Graison Luce Dauphinot Evelyne Paly Clothilde Mircher Aimé Ravel Yann Grattau Henri Bléhaut André Mégarbane Guy Dembour Bénédicte de Fréminville Renaud Touraine Nicole Créau Marie Claude Potier Jean Maurice Delabar Molecular signatures of cardiac defects in Down syndrome lymphoblastoid cell lines suggest altered ciliome and Hedgehog pathways. |
| description |
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. |
| format |
article |
| author |
Clémentine Ripoll Isabelle Rivals Emilie Ait Yahya-Graison Luce Dauphinot Evelyne Paly Clothilde Mircher Aimé Ravel Yann Grattau Henri Bléhaut André Mégarbane Guy Dembour Bénédicte de Fréminville Renaud Touraine Nicole Créau Marie Claude Potier Jean Maurice Delabar |
| author_facet |
Clémentine Ripoll Isabelle Rivals Emilie Ait Yahya-Graison Luce Dauphinot Evelyne Paly Clothilde Mircher Aimé Ravel Yann Grattau Henri Bléhaut André Mégarbane Guy Dembour Bénédicte de Fréminville Renaud Touraine Nicole Créau Marie Claude Potier Jean Maurice Delabar |
| author_sort |
Clémentine Ripoll |
| title |
Molecular signatures of cardiac defects in Down syndrome lymphoblastoid cell lines suggest altered ciliome and Hedgehog pathways. |
| title_short |
Molecular signatures of cardiac defects in Down syndrome lymphoblastoid cell lines suggest altered ciliome and Hedgehog pathways. |
| title_full |
Molecular signatures of cardiac defects in Down syndrome lymphoblastoid cell lines suggest altered ciliome and Hedgehog pathways. |
| title_fullStr |
Molecular signatures of cardiac defects in Down syndrome lymphoblastoid cell lines suggest altered ciliome and Hedgehog pathways. |
| title_full_unstemmed |
Molecular signatures of cardiac defects in Down syndrome lymphoblastoid cell lines suggest altered ciliome and Hedgehog pathways. |
| title_sort |
molecular signatures of cardiac defects in down syndrome lymphoblastoid cell lines suggest altered ciliome and hedgehog pathways. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/61fc4e0889fa44edbfb11babca003653 |
| work_keys_str_mv |
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