CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR SPLICE VARIANTS ARE NOT CONSERVED AND FAIL TO PRODUCE CHLORIDE CHANNELS

In the human CFTR only the rare exon 4- splice variant is conserved in mice. We have discovered two novel murine variants, exon 5- and exon 11b+. The exon 5- variant represents up to 40% of mRNA in all CFTR-exp ressing tissues and leaves the reading frame intact. The exon 11b+ var iant inserts a novel exon between exons 11 and 12 with expression rest ricted to the testis. Two variants of 11b have been found and both int roduce premature stop codons. When we expressed human CFTR variants la cking either exon 5 or exon 9 in HeLa cells, they failed to generate c AMP-mediated chloride transport, due to defective intracellular proces sing. The lack of conservation of splice variants between species and the inability of the more abundant splice variants to generate protein that is correctly processed argue against a physiological role and ma y simply represent aberrant splicing that is tolerated by the cell and organism.