Splicing factors induce cystic fibrosis transmembrane regulator exon 9 skipping through a nonevolutionary conserved intronic element - PubMed (original) (raw)
. 2000 Jul 14;275(28):21041-7.
doi: 10.1074/jbc.M910165199.
Affiliations
- PMID: 10766763
- DOI: 10.1074/jbc.M910165199
Free article
Splicing factors induce cystic fibrosis transmembrane regulator exon 9 skipping through a nonevolutionary conserved intronic element
F Pagani et al. J Biol Chem. 2000.
Free article
Abstract
In monosymptomatic forms of cystic fibrosis such as congenital bilateral absence of vas deferens, variations in the TG(m) and T(n) polymorphic repeats at the 3' end of intron 8 of the cystic fibrosis transmembrane regulator (CFTR) gene are associated with the alternative splicing of exon 9, which results in a nonfunctional CFTR protein. Using a minigene model system, we have previously shown a direct relationship between the TG(m)T(n) polymorphism and exon 9 splicing. We have now evaluated the role of splicing factors in the regulation of the alternative splicing of this exon. Serine-arginine-rich proteins and the heterogeneous nuclear ribonucleoprotein A1 induced exon skipping in the human gene but not in its mouse counterpart. The effect of these proteins on exon 9 exclusion was strictly dependent on the composition of the TG(m) and T(n) polymorphic repeats. The comparative and functional analysis of the human and mouse CFTR genes showed that a region of about 150 nucleotides, present only in the human intron 9, mediates the exon 9 splicing inhibition in association with exonic regulatory elements. This region, defined as the CFTR exon 9 intronic splicing silencer, is a target for serine-arginine-rich protein interactions. Thus, the nonevolutionary conserved CFTR exon 9 alternative splicing is modulated by the TG(m) and T(n) polymorphism at the 3' splice region, enhancer and silencer exonic elements, and the intronic splicing silencer in the proximal 5' intronic region. Tissue levels and individual variability of splicing factors would determine the penetrance of the TG(m)T(n) locus in monosymptomatic forms of cystic fibrosis.
Similar articles
- An intronic polypyrimidine-rich element downstream of the donor site modulates cystic fibrosis transmembrane conductance regulator exon 9 alternative splicing.
Zuccato E, Buratti E, Stuani C, Baralle FE, Pagani F. Zuccato E, et al. J Biol Chem. 2004 Apr 23;279(17):16980-8. doi: 10.1074/jbc.M313439200. Epub 2004 Feb 13. J Biol Chem. 2004. PMID: 14966131 - Functional analysis of cis-acting elements regulating the alternative splicing of human CFTR exon 9.
Niksic M, Romano M, Buratti E, Pagani F, Baralle FE. Niksic M, et al. Hum Mol Genet. 1999 Dec;8(13):2339-49. doi: 10.1093/hmg/8.13.2339. Hum Mol Genet. 1999. PMID: 10556281 - A T3 allele in the CFTR gene exacerbates exon 9 skipping in vas deferens and epididymal cell lines and is associated with Congenital Bilateral Absence of Vas Deferens (CBAVD).
Disset A, Michot C, Harris A, Buratti E, Claustres M, Tuffery-Giraud S. Disset A, et al. Hum Mutat. 2005 Jan;25(1):72-81. doi: 10.1002/humu.20115. Hum Mutat. 2005. PMID: 15580565 - Molecular pathology of the CFTR locus in male infertility.
Claustres M. Claustres M. Reprod Biomed Online. 2005 Jan;10(1):14-41. doi: 10.1016/s1472-6483(10)60801-2. Reprod Biomed Online. 2005. PMID: 15705292 Review. - Splicing mutations in the CFTR gene as therapeutic targets.
Deletang K, Taulan-Cadars M. Deletang K, et al. Gene Ther. 2022 Aug;29(7-8):399-406. doi: 10.1038/s41434-022-00347-0. Epub 2022 Jun 2. Gene Ther. 2022. PMID: 35650428 Free PMC article. Review.
Cited by
- Monomerization of TDP-43 is a key determinant for inducing TDP-43 pathology in amyotrophic lateral sclerosis.
Oiwa K, Watanabe S, Onodera K, Iguchi Y, Kinoshita Y, Komine O, Sobue A, Okada Y, Katsuno M, Yamanaka K. Oiwa K, et al. Sci Adv. 2023 Aug 4;9(31):eadf6895. doi: 10.1126/sciadv.adf6895. Epub 2023 Aug 4. Sci Adv. 2023. PMID: 37540751 Free PMC article. - Features of CFTR mRNA and implications for therapeutics development.
Jackson JJ, Mao Y, White TR Jr, Foye C, Oliver KE. Jackson JJ, et al. Front Genet. 2023 Apr 24;14:1166529. doi: 10.3389/fgene.2023.1166529. eCollection 2023. Front Genet. 2023. PMID: 37168508 Free PMC article. Review. - G-QINDER Tool: Bioinformatically Predicted Formation of Different Four-Stranded DNA Motifs from (GT)n and (GA)n Repeats.
Trizna L, Osif B, Víglaský V. Trizna L, et al. Int J Mol Sci. 2023 Apr 20;24(8):7565. doi: 10.3390/ijms24087565. Int J Mol Sci. 2023. PMID: 37108727 Free PMC article. - hnRNP A1 in RNA metabolism regulation and as a potential therapeutic target.
Feng J, Zhou J, Lin Y, Huang W. Feng J, et al. Front Pharmacol. 2022 Oct 21;13:986409. doi: 10.3389/fphar.2022.986409. eCollection 2022. Front Pharmacol. 2022. PMID: 36339596 Free PMC article. Review. - Characterization of the human TARDBP gene promoter.
Baralle M, Romano M. Baralle M, et al. Sci Rep. 2021 May 17;11(1):10438. doi: 10.1038/s41598-021-89973-z. Sci Rep. 2021. PMID: 34002018 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical
Molecular Biology Databases
Miscellaneous