Deep Intronic Mutation in SERPING1 Caused Hereditary Angioedema Through Pseudoexon Activation

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F20%3A00072618" target="_blank" >RIV/00159816:_____/20:00072618 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00209775:_____/20:N0000005 RIV/00216224:14110/20:00118619

Výsledek na webu

<a href="https://link.springer.com/article/10.1007%2Fs10875-020-00753-2" target="_blank" >https://link.springer.com/article/10.1007%2Fs10875-020-00753-2</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1007/s10875-020-00753-2" target="_blank" >10.1007/s10875-020-00753-2</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Deep Intronic Mutation in SERPING1 Caused Hereditary Angioedema Through Pseudoexon Activation

Popis výsledku v původním jazyce

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 &gt; 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.

Název v anglickém jazyce

Deep Intronic Mutation in SERPING1 Caused Hereditary Angioedema Through Pseudoexon Activation

Popis výsledku anglicky

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 &gt; 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30102 - Immunology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2020

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Clinical Immunology

ISSN

0271-9142

e-ISSN

—

Svazek periodika

40

Číslo periodika v rámci svazku

3

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

435-446

Kód UT WoS článku

000524860800002

EID výsledku v databázi Scopus

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