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Claudin-1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: A tight junction disease

Claudin-1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: A tight junction disease

Authors :
Hadj-Rabia, S.
Baala, L.
Vabres, P.
Hamel-Teillac, D.
Jacquemin, E.
Fabre, M.
Lyonnet, S.
de Prost, Y.
Munnich, A.
Hadchouel, M.
Smahi, A.
Source :
Gastroenterology; November 2004, Vol. 127 Issue: 5 p1386-1390, 5p
Publication Year :
2004

Abstract

Background & Aims: 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.

Details

Language :
English
ISSN :
00165085 and 15280012
Volume :
127
Issue :
5
Database :
Supplemental Index
Journal :
Gastroenterology
Publication Type :
Periodical
Accession number :
ejs9907340
Full Text :
https://doi.org/10.1053/j.gastro.2004.07.022