SHORT DIRECT REPEATS AT THE BREAKPOINTS OF A NOVEL LARGE DELETION IN THE CFTR GENE SUGGEST A LIKELY SLIPPED MISPAIRING MECHANISM

In the cystic fibrosis conductance transmembrane regulator (CFTR) gene a few small deletions and only a large, complex, 50-kb deletion have been described so far. We report a second large deletion, which had be en hypothesized in a patient affected by cystic fibrosis on the basis of an abnormal pattern of inheritance of the intragenic microsatellite s IVS17b/TA and IVS17b/CA. Southern blot analysis revealed the presenc e of an anomalous band in the patient and her father, in the region en compassing exons 13 - 19, approximately 0.6 kb shorten than the one pr esent in normal controls, in addition to the band of the correct size. Cloning and sequencing the DNA fragments spanning the region of inter est demonstrated the presence of a 703-bp deletion causing complete re moval of exon 17b in the paternal cystic fibrosis chromosome. This ana lysis revealed the presence of two short direct repeats flanking the b reakpoints. The 3' repeat partially overlapped the IVS 17b/CA microsat ellite and the number of CA repeated units present in the paternal cys tic fibrosis allele was the shortest ever found among chromosomes so f ar analyzed. These data may suggest that the mechanism for the generat ion of the deletion may have involved a slipped mispairing during DNA replication, which has not previously been described in the CFTR gene.