We created transgenic mice with a bacterial artificial chromosome (BAC) containing the human COL6A1 gene. In high-copy and low-copy transgenic lines, we found correct temporal and spatial expression of COL6A1 mRNA, paralleling the expression of the murine Col6a1 gene in a panel of nine adult and four fetal organs. The only exception was the fetal lung, in which the transgene was expressed poorly compared with the endogenous gene. Expression of COL6A1 mRNA from the transgene was copy number-dependent, and the increased gene dosage correlated with increased production of collagen VI alpha 1 in skin and heart, as indicated by Western blotting and immunohistochemistry. COL6A1 maps to Chromosome 21 and this gene has been a candidate for contributing to cardiac defects and skin abnormalities in Down syndrome. The low-copy and high-copy COL6A1 transgenics were born and survived in normal Mendelian proportions, without cardiac malformations or altered skin histology. These data indicate that the major promoter and enhancer sequences regulating COL6A1 expression are present in this 167-kb BAC clone. The lack of a strong cardiac or skin phenotype in the COL6A1 BAC-transgenic mice suggests that the increased expression of this gene does not, by itself, account for these phenotypes in Down syndrome.
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