Altered expression of mitochondrial and extracellular matrix genes in the heart of human fetuses with chromosome 21 trisomy.
BACKGROUND
The Down syndrome phenotype has been attributed to overexpression of chromosome 21 (Hsa21) genes. However, the expression profile of Hsa21 genes in trisomic human subjects as well as their effects on genes located on different chromosomes are largely unknown. Using oligonucleotide microarrays we compared the gene expression profiles of hearts of human fetuses with and without Hsa21 trisomy.


RESULTS
Approximately half of the 15,000 genes examined (87 of the 168 genes on Hsa21) were expressed in the heart at 18-22 weeks of gestation. Hsa21 gene expression was globally upregulated 1.5 fold in trisomic samples. However, not all genes were equally dysregulated and 25 genes were not upregulated at all. Genes located on other chromosomes were also significantly dysregulated. Functional class scoring and gene set enrichment analyses of 473 genes, differentially expressed between trisomic and non-trisomic hearts, revealed downregulation of genes encoding mitochondrial enzymes and upregulation of genes encoding extracellular matrix proteins. There were no significant differences between trisomic fetuses with and without heart defects.


CONCLUSIONS
We conclude that dosage-dependent upregulation of Hsa21 genes causes dysregulation of the genes responsible for mitochondrial function and for the extracellular matrix organization in the fetal heart of trisomic subjects. These alterations might be harbingers of the heart defects associated with Hsa21 trisomy, which could be based on elusive mechanisms involving genetic variability, environmental factors and/or stochastic events.
Conti
Anna
A
Dipartimento di Biologia e Patologia Cellulare e Molecolare, University Federico II, Napoli, Italy. anconti@unina.it <anconti@unina.it>
Fabbrini
Floriana
F
D'Agostino
Paola
P
Negri
Rosa
R
Greco
Dario
D
Genesio
Rita
R
D'Armiento
Maria
M
Olla
Carlo
C
Paladini
Dario
D
Zannini
Mariastella
M
Nitsch
Lucio
L
D004314:Down Syndrome; D005109:Extracellular Matrix / Q000235:genetics*; D020869:Gene Expression Profiling; D006321:Heart / Q000196:embryology*; D006801:Humans; D008928:Mitochondria / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics
D012333:RNA, Messenger