Characterization of two exon-skipping mutations (3120G{r_arrow}A, 3600G{r_arrow}A) in the CFTR gene
Journal Article
·
· American Journal of Human Genetics
OSTI ID:134783
- Hospital for Sick Children, Toronto (Canada)
- Children`s Hopsital of Western Ontario, London (Canada); and others
Many different types of mutations have been identified in the CFTR gene in patients with cystic fibrosis. Due to the large size of the gene (230 kb), CF mutations have been primarily detected by genomic DNA analysis. While some of the sequence alterations, such as nonsense and frameshift mutations, provide immediate clues to possible molecular consequence, others such as missense mutations are less apparent in their involvement in the disease. In our systematic scanning of the entire coding regions of the CFTR gene for a group of CF patients carrying unknown mutations, two different G to A substitutions located at the last nucleotide position of an exon were identified in two patients. The first one, 3120G{r_arrow}A, is located in exon 16 and the other one, 3600G{r_arrow}A, in exon 18 of the CFTR gene. Both of them are also located at the third position of the corresponding amino acid codon (CAG and TTC, respectively). As a result, the changes would not affect the encoded amino acids (Glu and Leu, respectively). To demonstrate that these are in fact pathologic mutations, we have investigated the CFTR transcripts in these two patients. The results of RT-PCR analysis revealed that aberrant splicing occurred in both cases: transcripts missing exon 16 and 18 were present in the 2 patients, respectively. No normal product was detectable from the 3120G{r_arrow}A and 3600G{r_arrow}A alleles, suggesting that the normal-sized products were exclusively derived from the {triangle}F508 mutant alleles in both of these patients. Hence, we conclude that both 3120G{r_arrow}A and 3600G{r_arrow}A mutations cause exon-skipping leading to premature termination and truncation of CFTR and that the altered G residue in each of these exons is probably part of the splice donor sequence important for efficient mRNA splicing.
- OSTI ID:
- 134783
- Report Number(s):
- CONF-941009--
- Journal Information:
- American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: Suppl.3 Vol. 55; ISSN AJHGAG; ISSN 0002-9297
- Country of Publication:
- United States
- Language:
- English
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