Deep Intronic Mutation in SERPING1 Caused Hereditary Angioedema
Through Pseudoexon Activation

J 2020

Deep Intronic Mutation in SERPING1 Caused Hereditary Angioedema Through Pseudoexon Activation

HUJOVÁ, Pavla, Přemysl SOUČEK, Lucie GRODECKÁ, Hana GROMBIŘÍKOVÁ, Barbora RAVČUKOVÁ et. al.

Základní údaje

Originální název

Deep Intronic Mutation in SERPING1 Caused Hereditary Angioedema Through Pseudoexon Activation

Autoři

HUJOVÁ, Pavla (203 Česká republika, domácí), Přemysl SOUČEK (203 Česká republika, domácí), Lucie GRODECKÁ (203 Česká republika), Hana GROMBIŘÍKOVÁ (203 Česká republika, domácí), Barbora RAVČUKOVÁ (203 Česká republika), Pavel KUKLÍNEK (203 Česká republika), Roman HAKL (203 Česká republika, domácí), Jiří LITZMAN (203 Česká republika, domácí) a Tomáš FREIBERGER (203 Česká republika, garant, domácí)

Vydání

Journal of Clinical Immunology, New York, Springer, 2020, 0271-9142

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30102 Immunology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 8.317

Kód RIV

RIV/00216224:14110/20:00118619

Organizační jednotka

Lékařská fakulta

DOI

http://dx.doi.org/10.1007/s10875-020-00753-2

UT WoS

000524860800002

Klíčová slova anglicky

Hereditary angioedema; SERPING1; pre-mRNA splicing; pseudoexon activation; donor splice site

Štítky

14110114, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 12. 5. 2021 13:45, Mgr. Tereza Miškechová

Anotace

V originále

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.

Návaznosti

NV16-34414A, projekt VaV

Název: Určení genových oblastí náchylných ke vzniku mutací ovlivňujících sestřih mRNA

NV18-05-00330, projekt VaV

Název: Genetická determinace závažnosti otoků podmíněných bradykininem u pacientů s hereditárním angioedémem

Investor: Ministerstvo zdravotnictví ČR, Genetická determinace závažnosti otoků podmíněných bradykininem u pacientů s hereditárním angioedémem

Citovat

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. 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.

@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.

Podrobný výpis o publikaci