Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance - PubMed (original) (raw)

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Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance

Emanuele Buratti et al. Am J Hum Genet. 2004 Jun.

No abstract available

Figures

Figure 1

Interaction of UG repeats with TDP-43, causing splicing inhibition. A, Diagram of the in vitro splicing assay. Boxes indicate exons, and the horizontal line indicates intronic sequences. In the UG6U5 construct, an A residue was removed in an attempt to keep the distance to the branch point. This was not possible for UG8 and UG12, and the original CFTR 3′ splice site was maintained. All constructs were transcribed by use of SP6 RNA polymerase and assayed with HeLa cells nuclear extracts (C4, Biotech) at time 0 hours and after 2 hours, in accordance with standard protocols. Unprocessed and spliced RNAs (left) were resolved on 6% denaturing gels. B, Spliced RNAs, present in the PY7(wt) and PY7(UG6U5) transcripts, reduced in the PY7(UG8U5) construct, and absent in PY7(UG12U5). C, Binding competition analysis. Unlabeled (UG)12 RNA was added in a 10-fold molar excess to the splicing mix, successfully rescuing splicing in the PY7(UG12U5) construct but having no effect on the PY7(wt) RNA. D, Western blot of normal (NE) and TDP-43 depleted (NE-TDP43) nuclear extracts. TDP-43 is completely absent after depletion. E, Depletion of TDP-43 from the nuclear extract induces the appearance of the spliced form (lane NE-TDP43) in the UG12-containing construct. The addition of purified GST-TDP-43 (300 ng) completely restores the splicing inhibition (lane NE-TDP43+ GST-TDP43).

Comment on

Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign.
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References

Electronic-Database Information

1. Online Mendelian Inheritance in Man (OMIM) http://www.ncbi.nlm.nih.gov/Omim

References

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Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance - PubMed (original) (raw)