MODULATION OF DISEASE SEVERITY IN CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR DEFICIENT MICE BY A SECONDARY GENETIC-FACTOR

Mice that have been made deficient for the cystic fibrosis transmembra ne conductance regulator (Cftr) usually die of intestinal obstruction, We have created Cftr-deficient mice and demonstrate prolonged surviva l among backcross and intercross progeny with different inbred strains , suggesting that modulation of disease severity is genetically determ ined. A genome scan showed that the major modifier locus maps near the centromere of mouse chromosome 7. Electrophysiological studies on mic e with prolonged survival show that the partial rectification of Cl- a nd Na+ ion transport abnormalities can be explained in part by up-regu lation of a calcium-activated Cl- conductance, Identification of modif ier genes in our Cftr(m1HSC)/Cft(rm1HSC) mice should provide important insight into the heterogeneous disease presentation observed among CF patients.