title: Claudin-1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: a tight junction disease.
abstract: OBJECTIVE
  Most human and animal cholestatic disorders are associated with changes in hepatocyte cytoskeleton and tight junctions (TJs). These changes are usually secondary and nonspecific phenomena, both in intra- and extrahepatic cholestasis. Recently, missense mutations in TJ protein 2 (ZO-2) have been identified in patients with familial hypercholanemia. In the liver, TJs separate bile flow from plasma and are composed of strands of claudins and occludin. We previously assigned a syndrome associating ichthyosis and neonatal sclerosing cholangitis (NISCH syndrome) to chromosome 3q27-q28. We considered claudin-1 to be a strong candidate gene based on its mapping to the minimum interval and on the expression pattern of the mouse ortholog.
  
  
  METHODS
  The 4 exons and intron-exon junctions of claudin-1 gene were amplified using standard polymerase chain reaction protocols and specific primers. Western blot analysis on cultured fibroblasts and immunohistochemistry on liver tissue section were performed using rabbit anti-claudin-1 antibodies.
  
  
  RESULTS
  We described in 4 patients, of 2 inbred kindred of Moroccan origin, a 2-bp deletion (200-201 TT) in exon 1 of the claudin-1 gene arising in a premature stop codon and resulting in total absence of claudin-1 protein in the liver and skin.
  
  
  CONCLUSIONS
  Lack of claudin-1 in NISCH syndrome may lead to increased paracellular permeability between epithelial cells. Bile duct injury may be related to the absence of claudin-1 expression in cholangiocytes. Our observation, in conjunction with ZO-2-associated hypercholanemia, emphasizes the role played by TJ components in hereditary cholestasis.
authors.affiliation: Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Smail
authors.initials: S
authors.lastname: Hadj-Rabia
authors.forename: Lekbir
authors.initials: L
authors.lastname: Baala
authors.forename: Pierre
authors.initials: P
authors.lastname: Vabres
authors.forename: Dominique
authors.initials: D
authors.lastname: Hamel-Teillac
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Jacquemin
authors.forename: Monique
authors.initials: M
authors.lastname: Fabre
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Yves
authors.initials: Y
authors.lastname: De Prost
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Michelle
authors.initials: M
authors.lastname: Hadchouel
authors.forename: Asma
authors.initials: A
authors.lastname: Smahi
mesh_terms: D015209:Cholangitis, Sclerosing / Q000150:complications / Q000151:congenital / Q000235:genetics*; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D062445:Claudin-1; D005260:Female; D006801:Humans; D007057:Ichthyosis / Q000150:complications / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D013577:Syndrome
chemical_list: C568108:CLDN1 protein, human; D062445:Claudin-1; C568113:Cldn1 protein, mouse; D008565:Membrane Proteins