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@article{1550500, author = {Souček, Přemysl and Réblová, Kamila and Kramárek, Michal and Radová, Lenka and Grymová, Tereza and Hujová, Pavla and Kováčová, Tatiana and Lexa, Matej and Grodecká, Lucie and Freiberger, Tomáš}, article_location = {PHILADELPHIA}, article_number = {10}, doi = {http://dx.doi.org/10.1080/15476286.2019.1630796}, keywords = {SMN1; cryptic splice sites; U1 snRNA; splicing-affecting mutation; 5 ' ss}, language = {eng}, issn = {1547-6286}, journal = {RNA BIOLOGY}, title = {High-throughput analysis revealed mutations' diverging effects on SMN1 exon 7 splicing}, url = {http://dx.doi.org/10.1080/15476286.2019.1630796}, volume = {16}, year = {2019} }
TY - JOUR ID - 1550500 AU - Souček, Přemysl - Réblová, Kamila - Kramárek, Michal - Radová, Lenka - Grymová, Tereza - Hujová, Pavla - Kováčová, Tatiana - Lexa, Matej - Grodecká, Lucie - Freiberger, Tomáš PY - 2019 TI - High-throughput analysis revealed mutations' diverging effects on SMN1 exon 7 splicing JF - RNA BIOLOGY VL - 16 IS - 10 SP - 1364-1376 EP - 1364-1376 PB - TAYLOR & FRANCIS INC SN - 15476286 KW - SMN1 KW - cryptic splice sites KW - U1 snRNA KW - splicing-affecting mutation KW - 5 ' ss UR - http://dx.doi.org/10.1080/15476286.2019.1630796 L2 - http://dx.doi.org/10.1080/15476286.2019.1630796 N2 - Splicing-affecting mutations can disrupt gene function by altering the transcript assembly. To ascertain splicing dysregulation principles, we modified a minigene assay for the parallel high-throughput evaluation of different mutations by next-generation sequencing. In our model system, all exonic and six intronic positions of the SMN1 gene's exon 7 were mutated to all possible nucleotide variants, which amounted to 180 unique single-nucleotide mutants and 470 double mutants. The mutations resulted in a wide range of splicing aberrations. Exonic splicing-affecting mutations resulted either in substantial exon skipping, supposedly driven by predicted exonic splicing silencer or cryptic donor splice site (5 ' ss) and de novo 5 ' ss strengthening and use. On the other hand, a single disruption of exonic splicing enhancer was not sufficient to cause major exon skipping, suggesting these elements can be substituted during exon recognition. While disrupting the acceptor splice site led only to exon skipping, some 5 ' ss mutations potentiated the use of three different cryptic 5 ' ss. Generally, single mutations supporting cryptic 5 ' ss use displayed better pre-mRNA/U1 snRNA duplex stability and increased splicing regulatory element strength across the original 5 ' ss. Analyzing double mutants supported the predominating splicing regulatory elements' effect, but U1 snRNA binding could contribute to the global balance of splicing isoforms. Based on these findings, we suggest that creating a new splicing enhancer across the mutated 5 ' ss can be one of the main factors driving cryptic 5 ' ss use. ER -
SOUČEK, Přemysl, Kamila RÉBLOVÁ, Michal KRAMÁREK, Lenka RADOVÁ, Tereza GRYMOVÁ, Pavla HUJOVÁ, Tatiana KOVÁČOVÁ, Matej LEXA, Lucie GRODECKÁ a Tomáš FREIBERGER. High-throughput analysis revealed mutations' diverging effects on SMN1 exon 7 splicing. \textit{RNA BIOLOGY}. PHILADELPHIA: TAYLOR \&{}amp; FRANCIS INC, 2019, roč.~16, č.~10, s.~1364-1376. ISSN~1547-6286. Dostupné z: https://dx.doi.org/10.1080/15476286.2019.1630796.
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