title: CLMP is required for intestinal development, and loss-of-function mutations cause congenital short-bowel syndrome.
abstract: OBJECTIVE
  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 610,000 K single-nucleotide polymorphism arrays to analyze the 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.
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Van Der Werf
authors.forename: Tara D
authors.initials: TD
authors.lastname: Wabbersen
authors.forename: Nai-Hua
authors.initials: NH
authors.lastname: Hsiao
authors.forename: Joana
authors.initials: J
authors.lastname: Paredes
authors.forename: Heather C
authors.initials: HC
authors.lastname: Etchevers
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kroisel
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.forename: Candice
authors.initials: C
authors.lastname: Babarit
authors.forename: Richard A
authors.initials: RA
authors.lastname: Schreiber
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hoffenberg
authors.forename: Michel
authors.initials: M
authors.lastname: Vekemans
authors.forename: Sirkka L
authors.initials: SL
authors.lastname: Zeder
authors.forename: Isabella
authors.initials: I
authors.lastname: Ceccherini
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Ana S
authors.initials: AS
authors.lastname: Ribeiro
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Te Meerman
authors.forename: Sven C D
authors.initials: SC
authors.lastname: van Ijzendoorn
authors.forename: Iain T
authors.initials: IT
authors.lastname: Shepherd
authors.forename: Joke B G M
authors.initials: JB
authors.lastname: Verheij
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D016466:CHO Cells; D002648:Child; D002675:Child, Preschool; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007421:Intestine, Small / Q000002:abnormalities* / Q000378:metabolism; D008297:Male; D009024:Morphogenesis; D020125:Mutation, Missense; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011991:Receptors, Virus / Q000235:genetics* / Q000378:metabolism; D012778:Short Bowel Syndrome / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D055815:Young Adult; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011991:Receptors, Virus; D029961:Zebrafish Proteins