Mutations in TJP2 cause progressive cholestatic liver disease

Abstract

Elucidating genetic causes of cholestasis has proved to be important in understanding the physiology and pathophysiology of the liver. Here we show that protein-truncating mutations in the tight junction protein 2 gene (TJP2) cause failure of protein localization and disruption of tight-junction structure, leading to severe cholestatic liver disease. These findings contrast with those in the embryonic-lethal knockout mouse, highlighting differences in redundancy in junctional complexes between organs and species.

Figure 1. rotein consequences of TJP2 mutation

Immunohistochemical staining of patient 5a (left panels), with control (right panels) for TJP2 (a), CLDN1 (b) and CLDN2 / BSEP (c) proteins. TJP2 expression (brown) is absent from cholangiocytes and canalicular margins. CLDN1 expression (brown) is markedly reduced at both sites. CLDN2 expression (brown), clustered within cytoplasm adjoining bile canaliculi (highlighted by BSEP, red), as has been shown previously. Hematoxylin counterstain; scale bar= 100 μm. (d) Western blot for CLDN1 and CLDN2 proteins isolated from liver biopsy tissues (1 control and 5 patients). Normalization was assessed using GAPDH as a loading control.