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Loss-of-Function of CLMP Is Associated With Congenital Short Bowel Syndrome and Impaired Intestinal Development
Shanshan Chen1, Juan Xu1, Yongtao Xiao1,2,3
1Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Abstract:
Coxsackie and adenovirus receptor-like membrane protein (CLMP) mutation is identified as a genetic risk factor of congenital short bowel syndrome (CSBS). However, the specific pathogenic mechanism remains unclear. This study aimed to explore the clinical manifestations, genetic characteristics, and molecular mechanisms underlying CSBS caused by CLMP mutations. Whole-exome sequencing was performed to determine the pathogenic gene mutations in children with CSBS and their family members. In addition, a zebrafish model was established by microinjecting morpholinos into zebrafish embryos to investigate the role of clmp in intestinal embryonic development. This was investigated by measuring the length of zebrafish, evaluating gastrointestinal motility, and performing qRT-PCR assays. Two children with CSBS had CLMP mutations, one with a c.244C>T (p.R82*) mutation and exons 3-5 deletion, and the other with a c.23T>A (p.L8*) mutation and exons 3-5 deletion. After knocking down clmp expression in zebrafish embryos, the intestinal length and the gastrointestinal motility decreased. Furthermore, the expression of smooth muscle-associated genes decreased significantly. Additionally, clmp mRNA partially rescued zebrafish defects caused by clmp morpholino knockdown. Clmp knockdown decreased intestinal transport dynamics and expression of smooth muscle-related genes in zebrafish. CLMP is expected to be a potential gene therapeutic target for CSBS.
Insights
Mutations in Coxsackie and adenovirus receptor-like membrane protein (CLMP) cause congenital short bowel syndrome (CSBS). CLMP is crucial for intestinal development, and its deficiency impairs gut motility and smooth muscle gene expression, suggesting it as a therapeutic target.
Area of Science:
- Genetics
- Developmental Biology
- Gastroenterology
Background:
- Congenital short bowel syndrome (CSBS) is linked to Coxsackie and adenovirus receptor-like membrane protein (CLMP) mutations.
- The precise molecular mechanisms driving CSBS pathogenesis due to CLMP mutations are not fully understood.
Purpose of the Study:
- To investigate the clinical, genetic, and molecular aspects of CSBS resulting from CLMP mutations.
- To elucidate the role of CLMP in intestinal embryonic development using a zebrafish model.
Main Methods:
- Whole-exome sequencing identified CLMP mutations in CSBS patients and families.
- A zebrafish model was created using morpholino knockdown of clmp to assess intestinal development and function.
- Measurements included zebrafish length, gastrointestinal motility, and qRT-PCR for gene expression.
Main Results:
- Two CSBS patients harbored distinct CLMP mutations (c.244C>T and c.23T>A), both involving exon deletions.
- Knockdown of clmp in zebrafish led to reduced intestinal length, impaired gastrointestinal motility, and decreased expression of smooth muscle-associated genes.
- Overexpression of clmp mRNA partially rescued the observed zebrafish phenotypes.
Conclusions:
- CLMP plays a critical role in embryonic intestinal development and function.
- CLMP deficiency impairs intestinal motility and smooth muscle development.
- CLMP represents a potential therapeutic target for congenital short bowel syndrome.
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