The SERPINB4 gene mutation identified in twin patients with Crohn’s disease impaires the intestinal epithelial cell functions
Abstract Crohn’s disease (CD) is a chronic inflammatory autoimmune disease of unknown etiology. To identify new targets related to the initiation of CD, we screened a pair of twins with CD, which is a rare phenomenon in the Chinese population, for genetic susceptibility factors. Whole-exome sequenci...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41598-025-87280-5 |
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| author | Xiao-Mei Ouyang Jun-Hui Lin Ying Lin Xian-Ling Zhao Ya‐Ni Huo Lai-Ying Liang Yong-Dong Huang Gui-Jing Xie Peng Mi Zhen-Yu Ye Bayasi Guleng |
| author_facet | Xiao-Mei Ouyang Jun-Hui Lin Ying Lin Xian-Ling Zhao Ya‐Ni Huo Lai-Ying Liang Yong-Dong Huang Gui-Jing Xie Peng Mi Zhen-Yu Ye Bayasi Guleng |
| author_sort | Xiao-Mei Ouyang |
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| description | Abstract Crohn’s disease (CD) is a chronic inflammatory autoimmune disease of unknown etiology. To identify new targets related to the initiation of CD, we screened a pair of twins with CD, which is a rare phenomenon in the Chinese population, for genetic susceptibility factors. Whole-exome sequencing (WES) of these patients revealed a mutation in their SERPINB4 gene. Therefore, we studied a wider clinical cohort of patients with CD or ulcerous colitis (UC), healthy individuals, and those with a family history of CD for this mutation by Sanger sequencing. The single-nucleotide difference in the SERPINB4 gene, which was unique to the twin patients with CD, led to the substitution of lysine by a glutamic acid residue. Functional analysis indicated that this mutation of SERPINB4 inhibited the proliferation, colony formation, wound healing, and migration of intestinal epithelial cells (IECs). Furthermore, mutation of SERPINB4 induced apoptosis and activated apoptosis-related proteins in IECs, and a caspase inhibitor significantly reduced these effects. Transcriptome sequencing revealed that the expression of genes encoding proinflammatory proteins (IL1B, IL6, IL17, IL24, CCL2, and CXCR2) and key proteins in the immune response (S100A9, MMP3, and MYC) was significantly upregulated during SERPINB4 mutant-induced apoptosis. Thus, the heterozygous SERPINB4 gene mutation causes the dysfunction of IECs, which would disrupt the intestinal epithelial barrier and contribute to the development of intestinal inflammation. The activation of SERPINB4 might represent a novel therapeutic target for inflammatory bowel disease. |
| format | Article |
| id | doaj-art-19cb7ebe0ea84a50b2ebdff5bddf512c |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-19cb7ebe0ea84a50b2ebdff5bddf512c2025-01-26T12:27:47ZengNature PortfolioScientific Reports2045-23222025-01-0115111510.1038/s41598-025-87280-5The SERPINB4 gene mutation identified in twin patients with Crohn’s disease impaires the intestinal epithelial cell functionsXiao-Mei Ouyang0Jun-Hui Lin1Ying Lin2Xian-Ling Zhao3Ya‐Ni Huo4Lai-Ying Liang5Yong-Dong Huang6Gui-Jing Xie7Peng Mi8Zhen-Yu Ye9Bayasi Guleng10Department of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen UniversityDepartment of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen UniversityDepartment of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen UniversityDepartment of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen UniversityDepartment of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen UniversityDepartment of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen UniversityDepartment of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen UniversityDepartment of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen UniversityDepartment of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen UniversityDepartment of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen UniversityDepartment of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen UniversityAbstract Crohn’s disease (CD) is a chronic inflammatory autoimmune disease of unknown etiology. To identify new targets related to the initiation of CD, we screened a pair of twins with CD, which is a rare phenomenon in the Chinese population, for genetic susceptibility factors. Whole-exome sequencing (WES) of these patients revealed a mutation in their SERPINB4 gene. Therefore, we studied a wider clinical cohort of patients with CD or ulcerous colitis (UC), healthy individuals, and those with a family history of CD for this mutation by Sanger sequencing. The single-nucleotide difference in the SERPINB4 gene, which was unique to the twin patients with CD, led to the substitution of lysine by a glutamic acid residue. Functional analysis indicated that this mutation of SERPINB4 inhibited the proliferation, colony formation, wound healing, and migration of intestinal epithelial cells (IECs). Furthermore, mutation of SERPINB4 induced apoptosis and activated apoptosis-related proteins in IECs, and a caspase inhibitor significantly reduced these effects. Transcriptome sequencing revealed that the expression of genes encoding proinflammatory proteins (IL1B, IL6, IL17, IL24, CCL2, and CXCR2) and key proteins in the immune response (S100A9, MMP3, and MYC) was significantly upregulated during SERPINB4 mutant-induced apoptosis. Thus, the heterozygous SERPINB4 gene mutation causes the dysfunction of IECs, which would disrupt the intestinal epithelial barrier and contribute to the development of intestinal inflammation. The activation of SERPINB4 might represent a novel therapeutic target for inflammatory bowel disease.https://doi.org/10.1038/s41598-025-87280-5Crohn’s diseaseSusceptibility geneSERPINB4Intestinal epithelial cellApoptosis |
| spellingShingle | Xiao-Mei Ouyang Jun-Hui Lin Ying Lin Xian-Ling Zhao Ya‐Ni Huo Lai-Ying Liang Yong-Dong Huang Gui-Jing Xie Peng Mi Zhen-Yu Ye Bayasi Guleng The SERPINB4 gene mutation identified in twin patients with Crohn’s disease impaires the intestinal epithelial cell functions Scientific Reports Crohn’s disease Susceptibility gene SERPINB4 Intestinal epithelial cell Apoptosis |
| title | The SERPINB4 gene mutation identified in twin patients with Crohn’s disease impaires the intestinal epithelial cell functions |
| title_full | The SERPINB4 gene mutation identified in twin patients with Crohn’s disease impaires the intestinal epithelial cell functions |
| title_fullStr | The SERPINB4 gene mutation identified in twin patients with Crohn’s disease impaires the intestinal epithelial cell functions |
| title_full_unstemmed | The SERPINB4 gene mutation identified in twin patients with Crohn’s disease impaires the intestinal epithelial cell functions |
| title_short | The SERPINB4 gene mutation identified in twin patients with Crohn’s disease impaires the intestinal epithelial cell functions |
| title_sort | serpinb4 gene mutation identified in twin patients with crohn s disease impaires the intestinal epithelial cell functions |
| topic | Crohn’s disease Susceptibility gene SERPINB4 Intestinal epithelial cell Apoptosis |
| url | https://doi.org/10.1038/s41598-025-87280-5 |
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