Back to Search
Start Over
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
- 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