CLMP Is Required for Intestinal Development, and Loss-of-Function Mutations Cause Congenital Short-Bowel Syndrome
- Authors
- Werf, C.S., Wabbersen, T.D., Hsiao, N.H., Paredes, J., Etchevers, H.C., Kroisel, P.M., Tibboel, D., Babarit, C., Schreiber, R.A., Hoffenberg, E.J., Vekemans, M., Zeder, S.L., Ceccherini, I., Lyonnet, S., Ribeiro, A.S., Seruca, R., Te Meerman, G.J., van Ijzendoorn, S.C., Shepherd, I.T., Verheij, J.B., and Hofstra, R.M.
- ID
- ZDB-PUB-120105-13
- Date
- 2012
- Source
- Gastroenterology 142(3): 453-462 (Journal)
- Registered Authors
- Shepherd, Iain T.
- Keywords
- ASAM, animal model, genetic analysis, embryology
- MeSH Terms
-
- Adolescent
- Adult
- Animals
- CHO Cells
- Child
- Child, Preschool
- Coxsackie and Adenovirus Receptor-Like Membrane Protein
- Cricetinae
- Cricetulus
- Disease Models, Animal
- Female
- Gene Expression Regulation, Developmental
- Genetic Predisposition to Disease
- Heterozygote
- Homozygote
- Humans
- Infant
- Infant, Newborn
- Intestine, Small/abnormalities*
- Intestine, Small/metabolism
- Male
- Morphogenesis
- Mutation, Missense*
- Phenotype
- Polymorphism, Single Nucleotide
- Receptors, Virus/genetics*
- Receptors, Virus/metabolism
- Short Bowel Syndrome/embryology
- Short Bowel Syndrome/genetics*
- Short Bowel Syndrome/metabolism
- Short Bowel Syndrome/pathology
- Transfection
- Young Adult
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 22155368 Full text @ Gastroenterology
Background & Aims
Short-bowel syndrome usually results from surgical resection of the small intestine for diseases such as intestinal atresias, volvulus, and necrotizing enterocolitis. Patients with congenital short-bowel syndrome (CSBS) are born with a substantial shortening of the small intestine, to a mean length of 50 cm, compared with a normal length at birth of 190–280 cm. They also are born with intestinal malrotation. Because CSBS occurs in many consanguineous families, it is considered to be an autosomal-recessive disorder. We aimed to identify and characterize the genetic factor causing CSBS.
Methods
We performed homozygosity mapping using 610 K single-nucleotide polymorphism arrays to analyze genomes of 5 patients with CSBS. After identifying a gene causing the disease, we determined its expression pattern in human embryos. We also overexpressed forms of the gene product that were and were not associated with CSBS in Chinese Hamster Ovary and T84 cells and generated a zebrafish model of the disease.
Results
We identified loss-of-function mutations in Coxsackie- and adenovirus receptor-like membrane protein (CLMP) in CSBS patients. CLMP is a tight-junction–associated protein that is expressed in the intestine of human embryos throughout development. Mutations in CLMP prevented its normal localization to the cell membrane. Knock-down experiments in zebrafish resulted in general developmental defects, including shortening of the intestine and the absence of goblet cells. Because goblet cells are characteristic for the midintestine in zebrafish, which resembles the small intestine in human beings, the zebrafish model mimics CSBS.
Conclusions
Loss-of-function mutations in CLMP cause CSBS in human beings, likely by interfering with tight-junction formation, which disrupts intestinal development. Furthermore, we developed a zebrafish model of CSBS.