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Am J Med Genet. 2002 May 15;109(4):298-305.

Beta 1 integrin activation mediates adhesive differences between trisomy 21 and non-trisomic fibroblasts on type VI collagen.

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Department of Pediatrics, Steele Memorial Children's Research Center, University of Arizona College of Medicine, Tucson, AZ 85724, USA.


Trisomy 21 (Down syndrome) is a common genetic condition with a high incidence of congenital heart defects (CHD), particularly those involving abnormal development of the embryonic atrioventricular (AV) canal. Type VI collagen (Col VI) is expressed in the developing AV canal extracellular matrix, and has been associated with trisomy 21 AV canal defects in human genetic studies. Although the molecular mechanisms linking Col VI and trisomy 21 AV canal defects are not well understood, a computer model predicts increased cell adhesiveness is responsible for these CHD. We compared integrin-mediated cell adhesive properties for skin fibroblasts isolated from trisomy 21 and non-trisomic individuals on Col VI, fibronectin (FN) and type I collagen (Col I). Cell lines demonstrate similar adhesion profiles to FN and Col I, but all trisomy 21 cells display increased adhesive capacity for Col VI compared to non-trisomic fibroblasts. Cell adhesion to type VI collagen was shown to be GRGDS independent, but beta(1) integrin family dependent. Function-blocking antibodies identified alpha(3)beta(1) as the predominant integrin mediating trisomy 21 and non-trisomic skin fibroblast adhesion on Col VI. Trisomy 21 and non-trisomic fibroblasts display similar expression levels for each of the integrin receptors examined. A beta(1) integrin-activating antibody augments non-trisomic cell adhesion on Col VI, but has no effect upon trisomy 21 fibroblasts. These results demonstrate that beta(1) integrin family members mediate trisomy 21 and non-trisomic skin fibroblast adhesion for Col VI. Altered activation state of the beta(1) integrin is a mechanism responsible for increased trisomy 21 cell adhesion on Col VI.

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