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Novel biallelic mutations in the DUOX2 gene underlying very early-onset inflammatory bowel disease: A case report
Reiko Kyodo1, Ichiro Takeuchi2, Satoshi Narumi3
1Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan; Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan.
Insights
Genetic variants in DUOX2 (dual oxidase 2) are linked to very early-onset inflammatory bowel disease (VEO-IBD). This case study identifies novel DUOX2 mutations potentially contributing to VEO-IBD development and disease severity.
Area of Science:
- Gastroenterology
- Genetics
- Immunology
Background:
- Genetic variants in DUOX2, encoding the catalytic subunit for hydrogen peroxide production, are implicated in very early-onset inflammatory bowel disease (VEO-IBD).
- DUOX2 mutations are associated with impaired barrier function and increased susceptibility to intestinal inflammation.
Observation:
- A 1-year-old boy presented with bloody diarrhea, diagnosed with VEO-IBD, exhibiting pancolitis and severe small intestinal ulcerations.
- Initial treatment with infliximab was effective but discontinued due to adverse reactions.
- Ustekinumab therapy initiated at age 7 led to sustained remission for over two years.
Findings:
- Whole-exome sequencing revealed compound heterozygous missense DUOX2 variants (p.[R1212H];[F1490Y]) of unknown significance.
- Functional studies demonstrated reduced protein expression and impaired hydrogen peroxide generation for both R1212H-DUOX2 and F1490Y-DUOX2 variants compared to wild-type.
- These novel, inherited DUOX2 mutations may represent molecular risk factors for VEO-IBD.
Implications:
- This case highlights the role of DUOX2 genetic variants in the pathogenesis of VEO-IBD.
- Understanding these genetic underpinnings can inform diagnostic approaches and therapeutic strategies for VEO-IBD.
- Further research into DUOX2 function in intestinal immunity is warranted.
Abstract:
Genetic variants affecting the function of dual oxidase 2 (DUOX2), the catalytic subunit of membrane-bound enzymes that produce hydrogen peroxide, are associated with very early-onset inflammatory bowel disease (VEO-IBD). We report the case of a 1-year-old boy diagnosed with VEO-IBD after presenting with bloody diarrhea. He had pancolitis and an extensive small intestinal ulcerative lesion at age 4 years. Infliximab treatment was successful but was discontinued due to delayed reaction. At age 7 years, treatment with ustekinumab was started, and remission has been maintained for more than 2 years. Whole-exome sequencing identified compound heterozygous missense DUOX2 variants of unknown significance (p.[R1212H];[F1490Y]). Protein expression in the whole-cell lysate and plasma membrane was lower in F1490Y-DUOX2 than in wild-type (WT)-DUOX2. Hydrogen peroxide generation upon ionomycin stimulation was lower in cells expressing R1212H-DUOX2 and F1490Y-DUOX2 than in those expressing WT-DUOX2. The novel, inherited, biallelic DUOX2 mutations may be molecular risk factors of VEO-IBD.
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