Abstract
BackgroundDown syndrome (DS), caused by trisomy of human chromosome 21 (HSA21), is the most common genetic birth defect. Congenital heart defects (CHD) are seen in 40% of DS children, and >50% of all atrioventricular canal defects in infancy are caused by trisomy 21, but the causative genes remain unknown.ResultsHere we show that aberrant adhesion and proliferation of DS cells can be reproduced using a transchromosomic model of DS (mouse fibroblasts bearing supernumerary HSA21). We also demonstrate a deacrease of cell migration in transchromosomic cells independently of their adhesion properties. We show that cell-autonomous proteome response to the presence of Collagen VI in extracellular matrix is strongly affected by trisomy 21.ConclusionThis set of experiments establishes a new model system for genetic dissection of the specific HSA21 gene-overdose contributions to aberrant cell migration, adhesion, proliferation and specific proteome response to collagen VI, cellular phenotypes linked to the pathogenesis of CHD.
Highlights
Down syndrome (DS), caused by trisomy of human chromosome 21 (HSA21), is the most common genetic birth defect
We show that increased DS cell adhesion to ColVI as matrix, aberrant proliferation of adhering DS cells, and aberrant cell migration can all be reproduced in a transchromosomic model of DS [14]
Transchromosomic models of DS offer a further advantage of the possibility of specific transcriptional silencing of a single gene from the supernumerary human chromosome while maintaining the trisomic expression of all other HSA21 genes [17], thereby assigning the causative genetic contribution for a phenotype to the trisomic overdose of a single HSA21 gene [17]
Summary
Down syndrome (DS), caused by trisomy of human chromosome 21 (HSA21), is the most common genetic birth defect. Congenital heart defects (CHD) are seen in 40% of DS children, and >50% of all atrioventricular canal defects in infancy are caused by trisomy 21, but the causative genes remain unknown. Down syndrome (DS), a congenital condition caused by the trisomy of human chromosome 21 (HSA21), is the most frequent chromosomal abnormality in live births associated with mental retardation and congenital heart defect (CHD) [1]. The pathology of DS is associated with a number of complex manifestations [1,2,3], the presence of a congenital heart defect (CHD) is the greatest risk factor for death during infancy. The crucial underlying process is the cellular (page number not for citation purposes)
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