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@article{1677116,
author = {Hujová, Pavla and Souček, Přemysl and Grodecká, Lucie and Grombiříková, Hana and Ravčuková, Barbora and Kuklínek, Pavel and Hakl, Roman and Litzman, Jiří and Freiberger, Tomáš},
article_location = {New York},
article_number = {3},
doi = {http://dx.doi.org/10.1007/s10875-020-00753-2},
keywords = {Hereditary angioedema; SERPING1; pre-mRNA splicing; pseudoexon activation; donor splice site},
language = {eng},
issn = {0271-9142},
journal = {Journal of Clinical Immunology},
title = {Deep Intronic Mutation in SERPING1 Caused Hereditary Angioedema Through Pseudoexon Activation},
url = {https://link.springer.com/article/10.1007/s10875-020-00753-2},
volume = {40},
year = {2020}
}
TY - JOUR
ID - 1677116
AU - Hujová, Pavla - Souček, Přemysl - Grodecká, Lucie - Grombiříková, Hana - Ravčuková, Barbora - Kuklínek, Pavel - Hakl, Roman - Litzman, Jiří - Freiberger, Tomáš
PY - 2020
TI - Deep Intronic Mutation in SERPING1 Caused Hereditary Angioedema Through Pseudoexon Activation
JF - Journal of Clinical Immunology
VL - 40
IS - 3
SP - 435-446
EP - 435-446
PB - Springer
SN - 02719142
KW - Hereditary angioedema
KW - SERPING1
KW - pre-mRNA splicing
KW - pseudoexon activation
KW - donor splice site
UR - https://link.springer.com/article/10.1007/s10875-020-00753-2
L2 - https://link.springer.com/article/10.1007/s10875-020-00753-2
N2 - Purpose Hereditary angioedema (HAE) is a rare autosomal dominant life-threatening disease characterized by low levels of C1 inhibitor (type I HAE) or normal levels of ineffective C1 inhibitor (type II HAE), typically occurring as a consequence of a SERPING1 mutation. In some cases, a causal mutation remains undetected after using a standard molecular genetic analysis. Results Here we show a long methodological way to the final discovery of c.1029 + 384A > G, a novel deep intronic mutation in intron 6 which is responsible for HAE type I in a large family and has not been identified by a conventional diagnostic approach. This mutation results in de novo donor splice site creation and subsequent pseudoexon inclusion, the mechanism firstly described to occur in SERPING1 in this study. We additionally discovered that the proximal part of intron 6 is a region potentially prone to pseudoexon-activating mutations, since natural alternative exons and additional cryptic sites occur therein. Indeed, we confirmed the existence of at least two different alternative exons in this region not described previously. Conclusions In conclusion, our results suggest that detecting aberrant transcripts, which are often low abundant because of nonsense-mediated decay, requires a modified methodological approach. We suggest SERPING1 intron 6 sequencing and/or tailored mRNA analysis to be routinely used in HAE patients with no mutation identified in the coding sequence.
ER -
HUJOVÁ, Pavla, Přemysl SOUČEK, Lucie GRODECKÁ, Hana GROMBIŘÍKOVÁ, Barbora RAVČUKOVÁ, Pavel KUKLÍNEK, Roman HAKL, Jiří LITZMAN a Tomáš FREIBERGER. Deep Intronic Mutation in SERPING1 Caused Hereditary Angioedema Through Pseudoexon Activation. \textit{Journal of Clinical Immunology}. New York: Springer, 2020, roč.~40, č.~3, s.~435-446. ISSN~0271-9142. Dostupné z: https://dx.doi.org/10.1007/s10875-020-00753-2.
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