Skipping of exon 12 as a consequence of a point mutation (1898+5G→T) in the cystic fibrosis transmembrane conductance regulator gene found in a consanguineous Chinese family

Abstract

A point mutation (1898+5G→T) located five base pairs downstream from the donor splice site in intron 12 of the CFTR gene has been identified in a consanguineous CF patient of Chinese origin. To determine if this nucleotide substitution could affect mRNA splicing, PCR analysis was performed with RNA isolated from the lymphoblastoid cell line of the mother of the deceased patient. While exon 12-minus transcript was detected in this sample, it was also found in individuals without 1898+5G→T, albeit in a smaller proportion. Using a sequence polymorphism associated with each of the two alleles in the mother, however, we showed that mutant transcript was almost exclusively produced by the 1898+5G→T allele. Skipping of exon 12 would result in the deletion of 29 amino acids from the first nucleotide binding domain of CFTR, rendering the protein non-functional. The possibility of a low level (≤2.5%) of normal transcript from the mutant allele cannot be excluded and it may explain the pancreatic sufficient phenotype of the patient. The 1898+5G→T mutation was found in two other CF patients of Chinese origin, but it was not detected in 192 CF chromosomes of Caucasian origin and 30 other chromosomes from Chinese individuals without a family history of CF.