Mutations in TJP2 cause progressive cholestatic liver disease

Sambrotta, Melissa; Strautnieks, Sandra; Papouli, Efterpi; Rushton, Peter; Clark, Barnaby; Parry, David; Logan, Clare V.; Newbury, Lucy J.; Kamath, Binita M.; Ling, Simon C.; Grammatikopoulos, Tassos; Wagner, Bart; Magee, John C.; Sokol, Ronald J.; Mieli‐Vergani, Giorgina; Smith, Joshua D.; Johnson, Colin A.; McClean, Patricia; Simpson, Michael A.; Knisely, Alexander S.; Bull, Laura N.; Rj, Thompson

doi:10.1038/ng.2918

Cited by 253 publications

(235 citation statements)

References 19 publications

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“…30,31 However, other junctional anomalies, especially in tight junction proteins, have recently been associated with cholestatic liver diseases, like progressive familial intrahepatic cholestasis. 32 Because g-catenin loss led to a more extensive hepatic injury during cholestasis, it will be relevant to characterize desmosomal proteins in cholestatic liver diseases as possible disease initiators or disease modifiers.…”

Section: G-catenin In Liver Pathophysiologymentioning

confidence: 99%

Mice with Hepatic Loss of the Desmosomal Protein γ-Catenin Are Prone to Cholestatic Injury and Chemical Carcinogenesis

Zhou

Pradhan‐Sundd

Poddar

et al. 2015

The American Journal of Pathology

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.g-Catenin, an important component of desmosomes, may also participate in Wnt signaling. Herein, we dissect the role of g-catenin in liver by generating conditional g-catenin knockout (KO) mice and assessing their phenotype after bile duct ligation (BDL) and diethylnitrosamine-induced chemical carcinogenesis. At baseline, KO and wild-type littermates showed comparable serum biochemistry, liver histology, and global gene expression. b-Catenin protein was modestly increased without any change in Wnt signaling. Desmosomes were maintained in KO, and despite no noticeable changes in gene expression, differential detergent fractionation revealed quantitative and qualitative changes in desmosomal cadherins, plaque proteins, and b-catenin. Enhanced association of b-catenin to desmoglein-2 and plakophilin-3 was observed in KO. When subjected to BDL, wild-type littermates showed specific changes in desmosomal protein expression. In KO, BDL deteriorated baseline compensatory changes, which manifested as enhanced injury and fibrosis. KO also showed enhanced tumorigenesis to diethylnitrosamine treatment because of Wnt activation, as also verified in vitro. g-Catenin overexpression in hepatoma cells increased its binding to T-cell factor 4 at the expense of b-catenineT-cell factor 4 association, induced unique target genes, affected Wnt targets, and reduced cell proliferation and viability. Thus, g-catenin loss in liver is basally well tolerated. However, after insults like BDL, these compensations at desmosomes fail, and KO show enhanced injury. Also, g-catenin negatively regulates tumor growth by affecting Wnt signaling. Plakoglobin or g-catenin belongs to the catenin family of proteins and is a component of desmosomes. Desmosomes are submembranous plaques that provide resistance to mechanical and shear stresses within a tissue and contribute to intercellular adhesion.1 Analogous to b-catenin at adherens junctions (AJs), g-catenin, like other desmosomal plaque proteins, such as desmoplakin (DP) and plakophilin (Pkp), adheres to neighboring cells by linking intracytoplasmic domains of transmembrane desmosomal cadherins like desmoglein (Dsg) and desmocollin (Dsc) to intermediate filaments.1 g-Catenin can also be a structural component of AJ, where it may be exchangeable with its close homolog, b-catenin. Both catenins also contain an armadillo domain and can bind the T-cell factor (TCF) family of transcription factors to participate in Wnt signaling. 2 We have previously identified an increase in g-catenin in the liver-specific b-catenin knockout (KO) mice, 3,4 where it was able to compensate for b-catenin loss at AJs without compromising desmosomes. However, g-catenin did not compensate for b-catenin loss in Wnt signaling, and b-catenin KO continued to lack liver-specific Wnt targets, such as glutamine synthetase (GS) and P450 2e1 and 1a2. 5The primary role of g-catenin in liver pathobiology remains unknown. We addressed the function of g-catenin in liver Supported by NIH grants 1R01DK62277 and 1R01DK100287 and Endowed Chair...

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Section: G-catenin In Liver Pathophysiologymentioning

confidence: 99%

Mice with Hepatic Loss of the Desmosomal Protein γ-Catenin Are Prone to Cholestatic Injury and Chemical Carcinogenesis

Zhou

Pradhan‐Sundd

Poddar

et al. 2015

The American Journal of Pathology

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“…One example of an unmet medical need is idiopathic liver disease, which remains a challenge in both pediatric and adult hepatology. We and others have shown the utility of whole-exome sequencing in the diagnosis of such patients (2)(3)(4)(5)(6). Children with unexplained liver disease who are the offspring of a consanguineous union are excellent candidates for recessive disease-causing mutations.…”

mentioning

confidence: 99%

ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment

Vilarinho

Sarı

Mazzacuva

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Acyl CoA Oxidase 2 (ACOX2) encodes branched-chain acyl-CoA oxidase, a peroxisomal enzyme believed to be involved in the metabolism of branched-chain fatty acids and bile acid intermediates. Deficiency of this enzyme has not been described previously. We report an 8-y-old male with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Exome sequencing revealed a previously unidentified homozygous premature termination mutation (p.Y69*) in ACOX2. Immunohistochemistry confirmed the absence of ACOX2 expression in the patient’s liver, and biochemical analysis showed marked elevation of intermediate bile acids upstream of ACOX2. These findings define a potentially treatable inborn error of bile acid biosynthesis caused by ACOX2 deficiency.

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“…Since in one third of patients with normal GGT cholestasis mutations in either ABCB11 or ATP8B1 have not been identified [26], a cohort of 33 cholestatic children with relatively low-serum GGT levels were studied recently [41]. Twelve patients from eight consanguineous families with novel protein truncating mutations in the TJP2 gene were identified.…”

Section: Tjp2 Deficiencymentioning

confidence: 99%