A woman with a family history of cystic fibrosis (CF) requested DNA analysis at 4 months of pregnancy. Since her brother died at age of 10 in 1986, it was necessary to perform DGGE screening of CFTR exons on DNA from the 2 parents. An aberrant heteroduplex pattern was observed for exon 10 amplified from genomic DNA of the mother (data reviewed but not shown). Direct sequencing revealed a T to C transition at nucleotide 1649, resulting in a threonine (codon ACC) for isoleucine (ATC) substitution at amino acid position 506. No restriction site is modified by this change. The father was found to carry the splicing mutation 2789 + 5G+A in exon 14b and the propositer inherited I506T.
The 1506T mutation replaces, in the first nucleotide-binding fold of the protein, a nonpolar hydrophobic by a polar hydrophile residue, which might result in alteration of the conformation and/or function of the domain. In absence of appropriate functional tests, it is not possible to prove that 1506T is a mutation causing disease. However, no other mutation was detected by DGGE screening in the obligate carrier mother of the index case, and this change has never been reported on normal chromosomes by the members of the CF Genetic Analysis Consortium.
One mutation (1506s) and two variants (1506V and I506M) have previously been reported for amino acid position 506 (Deufel et al., 1994;. While the 2 variants were represented by single cases, 1506s was detected in 4 patients with pancreatic insufficiency. Mutation 1506T has been found in only one family in a sample of 160 CF families from Southern France where 56 other mutations have been previously detected (Claustres et al., 1993 and unpublished data.)