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Background: Since the identification of the cystic fibrosis transmembrane regulator (CFTR) gene in 1989, many polymorphisms have been identified in cystic fibrosis (CF) or CFTR-related disorders (CFTR-RDs) patients and still remain to be characterized at the molecular level. These polymorphisms are difficult to classify as pathogenic or non-disease causing because the polymorphisms are either located in the coding region, but are synonymous, or are found in the intronic regions. Here we investigated the potential impact of the c.743 + 40A > G polymorphism within CFTR intron 6 on the alternative splicing. Indeed, this variant has been observed frequently in our examined patients. Moreover, a family carrying this variant exhibited CFTR-RD phenotype. Methods: By denaturing high pressure liquid phase chromatography (DHPLC) and sequencing, thirty of 293 subjects French origin carried the c.743 + 40A > G variant. Of these, 16 patients were affected by CF or CFTR-RD. Wild-type sequences and mutant CFTR intron 6 and its boundaries were inserted into the pTBNdeI hybride minigene and expressed in three different cell lines. After RT-PCR analysis of mRNA using specific primers, sequences of the minigene transcripts were obtained. Results: No aberrant splicing was detected with minigene carrying c.743 + 40A > G variant in all transfected cell lines. However, an alternative splicing in the positive control was detected with a minigene carrying the c.1392G > T + 1G > T mutation: 5 nucleotides were deleted from mRNA sequences, indicating that used cell lines are appropriate for studying the splicing. Conclusion: Transient transfections of a minigene containing the c.743 + 40A > G polymorphism showed no splicing errors, and thus this intronic alteration was finally classified as non-pathogenic. As it is always associated with c.2562T > G and c.4389G > A, or TG12-7T poly-morphisms, further experiments are needed to determine the role of these complex alleles in disease pathogenesis.

Minigene Analysis of the c.743 + 40A &gt; G Intronic Variant in the &lt;i&gt;CFTR&lt;/i&gt; Gene

Minigene Analysis of the c.743 + 40A > G Intronic Variant in the <i>CFTR</i> Gene