New deep intronic mutation c.1029+384 A>G in SERPING1 gene creates de novo donor splice site and causes aberrant splicing

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Authors

HUJOVÁ Pavla GROMBIŘÍKOVÁ Hana SOUČEK Přemysl GRODECKÁ Lucie RAVČUKOVÁ Barbora KUKLÍNEK Pavel HAKL Roman FREIBERGER Tomáš

Year of publication 2017
Type Conference abstract
MU Faculty or unit

Central European Institute of Technology

Citation
Description 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.
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