Functional studies associate novel DUOX2 gene variants detected in heterozygosity to Crohn’s disease

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F24%3A00585142" target="_blank" >RIV/68378050:_____/24:00585142 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00064203:_____/24:10478340 RIV/00216208:11130/24:10478340

Výsledek na webu

<a href="https://link.springer.com/article/10.1007/s11033-024-09317-8" target="_blank" >https://link.springer.com/article/10.1007/s11033-024-09317-8</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1007/s11033-024-09317-8" target="_blank" >10.1007/s11033-024-09317-8</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Functional studies associate novel DUOX2 gene variants detected in heterozygosity to Crohn’s disease

Popis výsledku v původním jazyce

Purpose: Crohn’s disease is a chronic gastrointestinal inflammatory disease with possible extraintestinal symptoms. There are predisposing genetic factors and even monogenic variants of the disorder. One of the possible genetic factors are variants of the DUOX2 gene. The protein product of the DUOX2 gene is a dual oxidase enzyme producing H2O2 in the bowel. Reduced H2O2 levels impact mucosal homeostasis and contribute to the development of inflammatory bowel disease. Thus far, only 19 patients with IBD with the DUOX2 variants have been described. Methods: Here we present a case report of an adolescent female diagnosed at eleven years of age with IBD that was subsequently reclassified as Crohn’s disease. She was treated with immunosuppressants and biological therapy but experienced additional complications. Her peripheral blood lymphocyte DNA was studied using massive parallel sequencing. Detected variants were functionally studied. Results: Whole exome sequencing found two novel DUOX2 gene variants: a de novo variant c.3646C>T, p.R1216W and a maternally inherited variant c.3391G>A, p.A1131T which were initially classified as variants of unknown significance. However, follow-up functional studies demonstrated that both DUOX2 variants led to impaired H2O2 generation, which led to their reclassification to the likely pathogenic class according to the ACMG.net. Therefore, we conclude that these variants are causative for the disease. Conclusions: Identifying novel variants in patients with Crohn’s disease and their families is important for precision medicine approaches and understanding of the pathogenesis of likely “monogenic” rare forms of inflammatory bowel disease.

Název v anglickém jazyce

Functional studies associate novel DUOX2 gene variants detected in heterozygosity to Crohn’s disease

Popis výsledku anglicky

Purpose: Crohn’s disease is a chronic gastrointestinal inflammatory disease with possible extraintestinal symptoms. There are predisposing genetic factors and even monogenic variants of the disorder. One of the possible genetic factors are variants of the DUOX2 gene. The protein product of the DUOX2 gene is a dual oxidase enzyme producing H2O2 in the bowel. Reduced H2O2 levels impact mucosal homeostasis and contribute to the development of inflammatory bowel disease. Thus far, only 19 patients with IBD with the DUOX2 variants have been described. Methods: Here we present a case report of an adolescent female diagnosed at eleven years of age with IBD that was subsequently reclassified as Crohn’s disease. She was treated with immunosuppressants and biological therapy but experienced additional complications. Her peripheral blood lymphocyte DNA was studied using massive parallel sequencing. Detected variants were functionally studied. Results: Whole exome sequencing found two novel DUOX2 gene variants: a de novo variant c.3646C>T, p.R1216W and a maternally inherited variant c.3391G>A, p.A1131T which were initially classified as variants of unknown significance. However, follow-up functional studies demonstrated that both DUOX2 variants led to impaired H2O2 generation, which led to their reclassification to the likely pathogenic class according to the ACMG.net. Therefore, we conclude that these variants are causative for the disease. Conclusions: Identifying novel variants in patients with Crohn’s disease and their families is important for precision medicine approaches and understanding of the pathogenesis of likely “monogenic” rare forms of inflammatory bowel disease.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/LM2018132" target="_blank" >LM2018132: Národní centrum lékařské genomiky</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

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

Název periodika

Molecular Biology Reports

ISSN

0301-4851

e-ISSN

1573-4978

Svazek periodika

51

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

7

Strana od-do

399

Kód UT WoS článku

001178229900007

EID výsledku v databázi Scopus

2-s2.0-85187176218