Sangermano, Riccardo and Garanto, Alejandro and Khan, Mubeen and Runhart, Esmee H. and Bauwens, Miriam and Bax, Nathalie M. and van den Born, L. Ingeborgh and Khan, Muhammad Imran and Cornelis, Stephanie S. and Verheij, Joke B. G. M. and Pott, Jan-Willem R. and Thiadens, Alberta A. H. J. and Klaver, Caroline C. W. and Puech, Bernard and Meunier, Isabelle and Naessens, Sarah and Arno, Gavin and Fakin, Ana and Carss, Keren J. and Raymond, F. Lucy and Webster, Andrew R. and Dhaenens, Claire-Marie and Stoehr, Heidi and Grassmann, Felix and Weber, Bernhard H. F. and Hoyng, Carel B. and De Baere, Elfride and Albert, Silvia and Collin, Rob W. J. and Cremers, Frans P. M. (2019) Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides. GENETICS IN MEDICINE, 21 (8). pp. 1751-1760. ISSN 1098-3600, 1530-0366
Full text not available from this repository. (Request a copy)Abstract
Purpose: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability. Methods: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects. Results: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects. Conclusion: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | IN-VITRO; MUTATIONS; GENE; REVEALS; POPULATION; ABCA4; antisense oligonucleotide; deep-intronic variant; missing heritability; Stargardt disease |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 07 Apr 2020 06:09 |
| Last Modified: | 07 Apr 2020 06:09 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26549 |
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