Claudin-1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: a tight junction disease.
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.
Hadj-Rabia
Smail
S
Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France.
Baala
Lekbir
L
Vabres
Pierre
P
Hamel-Teillac
Dominique
D
Jacquemin
Emmanuel
E
Fabre
Monique
M
Lyonnet
Stanislas
S
De Prost
Yves
Y
Munnich
Arnold
A
Hadchouel
Michelle
M
Smahi
Asma
A
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
C568108:CLDN1 protein, human; D062445:Claudin-1; C568113:Cldn1 protein, mouse; D008565:Membrane Proteins