PRODUCTION OF A SEVERE CYSTIC-FIBROSIS MUTATION IN MICE BY GENE TARGETING

We have used gene targeting in embryonic stem cells to introduce an HP RT mini-gene into the coding sequence of the murine cystic fibrosis ge ne (cftr). This insertion introduces a termination codon in frame with the cftr coding sequence to terminate prematurely the CFTR protein wi thin the first nucleotide binding domain. Animals homozygous for the c ftr disruption fail to thrive and display a range of symptoms includin g meconium ileus, distal intestinal obstructions, gastrointestinal muc us accumulation and blockage of pancreatic ducts. The animals also sho w lacrimal gland pathology. Tracheal and caecal transepithelial curren t measurements demonstrate the lack of a cAMP activatable Cl- channel. These animals will prove useful for the evaluation of new therapeutic drugs and gene therapy strategies.