Mutations in TJP2 cause progressive cholestatic liver disease

Melissa Sambrotta; Sandra Strautnieks; Efterpi Papouli; Peter Rushton; Barnaby E Clark; David A Parry; Clare V Logan; Lucy J Newbury; Binita M Kamath; Simon Ling; Tassos Grammatikopoulos; Bart E Wagner; John C Magee; Ronald J Sokol; Giorgina Mieli-Vergani; University of Washington Center for Mendelian Genomics; Joshua D Smith; Colin A Johnson; Patricia McClean; Michael A Simpson; A S Knisely; Laura N Bull; Richard J Thompson

doi:10.1038/ng.2918

Mutations in TJP2 cause progressive cholestatic liver disease

Nat Genet. 2014 Apr;46(4):326-8. doi: 10.1038/ng.2918. Epub 2014 Mar 9.

Authors

Melissa Sambrotta¹, Sandra Strautnieks², Efterpi Papouli³, Peter Rushton⁴, Barnaby E Clark⁴, David A Parry⁵, Clare V Logan⁵, Lucy J Newbury⁶, Binita M Kamath⁷, Simon Ling⁷, Tassos Grammatikopoulos⁸, Bart E Wagner⁹, John C Magee¹⁰, Ronald J Sokol¹¹, Giorgina Mieli-Vergani⁸; University of Washington Center for Mendelian Genomics; Joshua D Smith¹², Colin A Johnson⁵, Patricia McClean¹³, Michael A Simpson¹⁴, A S Knisely², Laura N Bull¹⁵, Richard J Thompson⁸

Affiliations

¹ Institute of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, King's College London School of Medicine, London, UK.
² Institute of Liver Studies, King's College Hospital, London, UK.
³ Biomedical Research Centre (BRC) Genomics Core Facility, Guy's and St Thomas' National Health Service (NHS) Foundation Trust and King's College London, London, UK.
⁴ King's College Hospital NHS Foundation Trust, Department of Haematological Medicine, London, UK.
⁵ Leeds Institute of Molecular Medicine, St James's University Hospital, University of Leeds, Leeds, UK.
⁶ Renal Sciences, Division of Transplantation Immunology and Mucosal Biology, King's College London School of Medicine, London, UK.
⁷ 1] Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
⁸ 1] Institute of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, King's College London School of Medicine, London, UK. [2] Paediatric Liver, GI and Nutrition Centre, King's College Hospital, London, UK.
⁹ Histopathology Department, Royal Hallamshire Hospital, Sheffield, UK.
¹⁰ Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.
¹¹ Department of Pediatrics, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, Colorado, USA.
¹² Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
¹³ Children's Liver and Gastroenterology Unit, Leeds General Infirmary, Leeds, UK.
¹⁴ Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, UK.
¹⁵ 1] Liver Center Laboratory, Department of Medicine, University of California, San Francisco, San Francisco, California, USA. [2] Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.

PMID: 24614073
PMCID: PMC4061468
DOI: 10.1038/ng.2918

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.

Publication types

Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Cholestasis, Intrahepatic / genetics*
Cholestasis, Intrahepatic / physiopathology
High-Throughput Nucleotide Sequencing
Humans
Immunoblotting
Immunohistochemistry
Mice
Mice, Knockout
Microscopy, Electron, Transmission
Models, Biological
Molecular Sequence Data
Mutation / genetics*
Pedigree
Real-Time Polymerase Chain Reaction
Sequence Alignment
Species Specificity
Tight Junctions / genetics
Tight Junctions / pathology*
Zonula Occludens-2 Protein / genetics*

Substances

TJP2 protein, human
Zonula Occludens-2 Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding