Mutations in TJP2, Encoding Zona Occludens 2, and Liver Disease

Overview

Journal Tissue Barriers

Specialties Anatomy & Histology
Biology
Physiology

Date 2015 Oct 10

PMID 26451340

Citations 25

Authors

Melissa Sambrotta

Richard J Thompson

Affiliations

Soon will be listed here.

Abstract

Progressive familial intrahepatic cholestasis is a clinical description of a phenotype, which we now realize has several different genetic aetiologies. The identification of the underlying genetic defects has helped to elucidate important aspects of liver physiology. The latest addition to this family of diseases is tight junction protein 2 (TJP2) deficiency. This protein is also known as zona occludens 2 (ZO-2). The patients, so far presented, all have homozygous, protein-truncating mutations. A complete absence of this protein was demonstrated. These children presented with severe liver disease, some manifesting extrahepatic features. By contrast, embryonic-lethality was seen in ZO-2 knockout mice. This discovery highlights important differences, not just between species, but also between different epithelia in humans. This commentary discusses the recently presented findings, and some of the issues that arise.

Citing Articles

A Novel Compound Heterozygous Mutation in Progressive Familial Intrahepatic Cholestasis (PFIC) 4: A Rare Case Report With Literature Review.

Pandey D, Chandnani S, Gandhi H, Vishal M, Rathi P Cureus. 2024; 16(11):e73927.

PMID: 39697951 PMC: 11654999. DOI: 10.7759/cureus.73927.

Progressive familial intrahepatic cholestasis type 4: a case report.

Abokandil M, Waheeb S, Zaghloul W, Abdelgawad M, Abdelhady M, Mansy M J Med Case Rep. 2024; 18(1):434.

PMID: 39243110 PMC: 11380191. DOI: 10.1186/s13256-024-04662-5.

Progressive Familial Intrahepatic Cholestasis: A Descriptive Study in a Tertiary Care Center.

Alsohaibani F, Peedikayil M, Alfadley A, Aboueissa M, Abaalkhail F, Alqahtani S Int J Hepatol. 2023; 2023:1960152.

PMID: 37520499 PMC: 10374379. DOI: 10.1155/2023/1960152.

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency.

Felzen A, van Wessel D, Gonzales E, Thompson R, Jankowska I, Shneider B JHEP Rep. 2023; 5(2):100626.

PMID: 36687469 PMC: 9852554. DOI: 10.1016/j.jhepr.2022.100626.

Human iPSC-derived hepatocyte system models cholestasis with tight junction protein 2 deficiency.

Li C, Ogawa H, Ng S, Chen X, Kishimoto E, Sakabe K JHEP Rep. 2022; 4(4):100446.

PMID: 35284810 PMC: 8904612. DOI: 10.1016/j.jhepr.2022.100446.

References

Neu-Yilik G, Amthor B, Gehring N, Bahri S, Paidassi H, Hentze M . Mechanism of escape from nonsense-mediated mRNA decay of human beta-globin transcripts with nonsense mutations in the first exon. RNA. 2011; 17(5):843-54. PMC: 3078734. DOI: 10.1261/rna.2401811. View

Lykavieris P, van Mil S, Cresteil D, Fabre M, Hadchouel M, Klomp L . Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation. J Hepatol. 2003; 39(3):447-52. DOI: 10.1016/s0168-8278(03)00286-1. View

de Vree J, Jacquemin E, Sturm E, Cresteil D, Bosma P, Aten J . Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci U S A. 1998; 95(1):282-7. PMC: 18201. DOI: 10.1073/pnas.95.1.282. View

Sambrotta M, Strautnieks S, Papouli E, Rushton P, Clark B, Parry D . Mutations in TJP2 cause progressive cholestatic liver disease. Nat Genet. 2014; 46(4):326-8. PMC: 4061468. DOI: 10.1038/ng.2918. View

Kuipers F, Bloks V, Groen A . Beyond intestinal soap--bile acids in metabolic control. Nat Rev Endocrinol. 2014; 10(8):488-98. DOI: 10.1038/nrendo.2014.60. View

Strautnieks S, Bull L, Knisely A, Kocoshis S, Dahl N, Arnell H . A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet. 1998; 20(3):233-8. DOI: 10.1038/3034. View

Kervestin S, Jacobson A . NMD: a multifaceted response to premature translational termination. Nat Rev Mol Cell Biol. 2012; 13(11):700-12. PMC: 3970730. DOI: 10.1038/nrm3454. View

Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S . Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol. 1998; 141(7):1539-50. PMC: 2132999. DOI: 10.1083/jcb.141.7.1539. View

Kim M, Kim Y, Sagong B, Cho H, Bae J, Kim J . Genetic analysis of genes related to tight junction function in the Korean population with non-syndromic hearing loss. PLoS One. 2014; 9(4):e95646. PMC: 3994078. DOI: 10.1371/journal.pone.0095646. View

10.

Bull L, Van Eijk M, Pawlikowska L, DeYoung J, Juijn J, Liao M . A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet. 1998; 18(3):219-24. DOI: 10.1038/ng0398-219. View

11.

Tapia R, Huerta M, Islas S, Avila-Flores A, Lopez-Bayghen E, Weiske J . Zona occludens-2 inhibits cyclin D1 expression and cell proliferation and exhibits changes in localization along the cell cycle. Mol Biol Cell. 2008; 20(3):1102-17. PMC: 2633389. DOI: 10.1091/mbc.e08-03-0277. View

12.

Singh D, Solan J, Taffet S, Javier R, Lampe P . Connexin 43 interacts with zona occludens-1 and -2 proteins in a cell cycle stage-specific manner. J Biol Chem. 2005; 280(34):30416-21. PMC: 3501655. DOI: 10.1074/jbc.M506799200. View

13.

Hadj-Rabia S, Baala L, Vabres P, Hamel-Teillac D, Jacquemin E, Fabre M . Claudin-1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: a tight junction disease. Gastroenterology. 2004; 127(5):1386-90. DOI: 10.1053/j.gastro.2004.07.022. View

14.

Walsh T, Pierce S, Lenz D, Brownstein Z, Dagan-Rosenfeld O, Shahin H . Genomic duplication and overexpression of TJP2/ZO-2 leads to altered expression of apoptosis genes in progressive nonsyndromic hearing loss DFNA51. Am J Hum Genet. 2010; 87(1):101-9. PMC: 2896780. DOI: 10.1016/j.ajhg.2010.05.011. View

15.

Hewitt K, Agarwal R, Morin P . The claudin gene family: expression in normal and neoplastic tissues. BMC Cancer. 2006; 6:186. PMC: 1538620. DOI: 10.1186/1471-2407-6-186. View

16.

Carlton V, Harris B, Puffenberger E, Batta A, Knisely A, Robinson D . Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT. Nat Genet. 2003; 34(1):91-6. DOI: 10.1038/ng1147. View

17.

Xu J, Kausalya P, Phua D, Mohamed Ali S, Hossain Z, Hunziker W . Early embryonic lethality of mice lacking ZO-2, but Not ZO-3, reveals critical and nonredundant roles for individual zonula occludens proteins in mammalian development. Mol Cell Biol. 2008; 28(5):1669-78. PMC: 2258782. DOI: 10.1128/MCB.00891-07. View

18.

Davit-Spraul A, Fabre M, Branchereau S, Baussan C, Gonzales E, Stieger B . ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology. 2010; 51(5):1645-55. DOI: 10.1002/hep.23539. View

19.

Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A, Tilg H . Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology. 2004; 127(1):261-74. DOI: 10.1053/j.gastro.2004.04.009. View

20.

Knisely A, Strautnieks S, Meier Y, Stieger B, Byrne J, Portmann B . Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology. 2006; 44(2):478-86. DOI: 10.1002/hep.21287. View