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@proceedings{1404106, author = {Hujová, Pavla and Grombiříková, Hana and Souček, Přemysl and Grodecká, Lucie and Ravčuková, Barbora and Kuklínek, Pavel and Hakl, Roman and Freiberger, Tomáš}, booktitle = {ESHG, Dánsko}, keywords = {splicing; hereditary angioedema; pseudoexon}, language = {eng}, title = {New deep intronic mutation c.1029+384 A>G in SERPING1 gene creates de novo donor splice site and causes aberrant splicing}, year = {2017} }
TY - CONF ID - 1404106 AU - Hujová, Pavla - Grombiříková, Hana - Souček, Přemysl - Grodecká, Lucie - Ravčuková, Barbora - Kuklínek, Pavel - Hakl, Roman - Freiberger, Tomáš PY - 2017 TI - New deep intronic mutation c.1029+384 A>G in SERPING1 gene creates de novo donor splice site and causes aberrant splicing KW - splicing KW - hereditary angioedema KW - pseudoexon N2 - Traditionally, the diagnostics of hereditary diseases is primarily focused on detection of mutation in exons or immediately flanking regions of introns. However, the occurrence of the cases with no detected mutations is not unusual. The diagnostic process in these cases is very variable and may include analyses at mRNA level and/or applying next generation sequencing approach. In this work, we have investigated a family diagnosed with hereditary angioedema with no detected exonic or flanking intronic mutation in SERPING1 gene encoding C1 inhibitor protein. Nevertheless, subsequent capillary analysis of the blood-derived mRNA revealed a low abundant variant prolonged by approximately 89 bp, which had not been detected using standard gel electrophoresis. After intron sequencing, mutation c.1029+384 A>G was found 384 bp downstream of the exon 6, which co-segregated with HAE phenotype in all available family members. According to in silico splicing analysis the mutation results in strong donor splice site creation with possible subsequent pseudoexon activation. This hypothesis was confirmed by sequencing of the patient's cDNA using a specific primer hybridizing to the predicted pseudoexon and independently by a minigene analysis. The low amount of the aberrant transcript variant may be explained by its degradation by a natural mechanism called nonsense mediated decay. In conclusion, these findings highlight the importance of mRNA analysis and minigene assay as useful approaches in diagnostics. ER -
HUJOVÁ, Pavla, Hana GROMBIŘÍKOVÁ, Přemysl SOUČEK, Lucie GRODECKÁ, Barbora RAVČUKOVÁ, Pavel KUKLÍNEK, Roman HAKL a Tomáš FREIBERGER. New deep intronic mutation c.1029+384 A\&{}gt;G in SERPING1 gene creates de novo donor splice site and causes aberrant splicing. In \textit{ESHG, Dánsko}. 2017.
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