Journal article

Spontaneous retrotransposon insertion into TNF 3'UTR causes heart valve disease and chronic polyarthritis

Derek Lacey, Peter Hickey, Benedicta D Arhatari, Lorraine A O'Reilly, Leona Rohrbeck, Helen Kiriazis, Xiao-Jun Du, Philippe Bouillet

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | NATL ACAD SCIENCES | Published : 2015

Abstract

Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic inflammatory diseases that together affect 2-3% of the population. RA and AS predominantly involve joints, but heart disease is also a common feature in RA and AS patients. Here we have studied a new spontaneous mutation that causes severe polyarthritis in bone phenotype spontaneous mutation 1 (BPSM1) mice. In addition to joint destruction, mutant mice also develop aortic root aneurism and aorto-mitral valve disease that can be fatal depending on the genetic background. The cause of the disease is the spontaneous insertion of a retrotransposon into the 3' untranslated region (3'UTR) of the tumor necrosis factor (TNF), whic..

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Grants

Awarded by Australian National Health and Medical Research Council (NHMRC)


Awarded by Leukemia and Lymphoma Society (Specialized Center of Research Grant)


Funding Acknowledgements

We thank J. Stanley, S. O'Connor, T. Bertenis, and G. Siciliano for animal care and expertise; S. Wilcox, M. Robati, and A. Lin for technical assistance; J. Corbin for automated blood analysis; B. Malissen (Marseille Luminy) for CD3 epsilon KO mice; M. Reth (Max-Planck Institute of Immunobiology) for Mb1-cre KI mice; S. Akira (Osaka University Immunology Frontier Research Center) for Myd-88 KO mice; T. Mak (The Campbell Family Institute for Breast Cancer Research) for TNFR1 KO mice; I. Wicks for GMCSF KO mice; J. Silke for TNF KO mice; G. Thomas for TNF<SUP>Delta ARE</SUP> mice; and A. Strasser for critically reviewing the manuscript. This work was supported by the Australian National Health and Medical Research Council (NHMRC; Program Grant 461221, Research Fellowship 1042629); the Leukemia and Lymphoma Society (Specialized Center of Research Grant 7015); the Arthritis Australia Zimmer fellowship; and infrastructure support from the NHMRC (Independent Research Institutes Infrastructure Support Scheme) and the Victorian State Government (Operational Infrastructure Support).