Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans (original) (raw)

Nature volume 439, pages 851–855 (2006)Cite this article

Abstract

Identification of the genes underlying complex phenotypes and the definition of the evolutionary forces that have shaped eukaryotic genomes are among the current challenges in molecular genetics1,2,3. Variation in gene copy number is increasingly recognized as a source of inter-individual differences in genome sequence and has been proposed as a driving force for genome evolution and phenotypic variation3,4,5. Here we show that copy number variation of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the newly described, rat-specific Fcgr3 paralogue, Fcgr3-related sequence (Fcgr3-rs), as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B, an orthologue of rat Fcgr3, was associated with glomerulonephritis in the autoimmune disease systemic lupus erythematosus. The finding that gene copy number polymorphism predisposes to immunologically mediated renal disease in two mammalian species provides direct evidence for the importance of genome plasticity in the evolution of genetically complex phenotypes, including susceptibility to common human disease.

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Acknowledgements

We acknowledge intramural funding from the CSC, and support from the Wellcome Trust Cardiovascular Functional Genomics award, the British Heart Foundation and the Medical Research Council. P.R.C. is a Medical Research Council Clinical Fellow. We thank E. Sodergren and G. Weinstock for BAC clone DNA; H. Hedrich, A. Dominiczak and J. Rapp for rat genomic DNA; T. Serikawa and the National Bio Resource Project in Japan for rat strains and genomic DNA; B. Foxwell for bicistronic vector; and M. Botto, B. Morley, P. Froguel, C. Shoulders and S. Cook for constructive criticism of the manuscript. We acknowledge the CSC Genomics Laboratory for DNA sequencing, and bioinformatics support from M. Müller, N. J. Dickens and the Imperial College Bioinformatics Support Service. Author Contributions The study was conceived and funded by T.J.A., H.T.C. and C.D.P. H.T.C., J.S., P.R.C. and D.J.E. carried out the rodent phenotyping. T.J.A., M.D., P.J.N., P.R.C. and J.F. carried out the rodent linkage studies. T.J.A., R.D., M.D.J., J.M., A.J.M., M.D.H., S.G.P. and K.S.-R. carried out the genomic analysis of rat and human Fcgr3. Cellular immunology studies were carried out by R.D., J.J.B., M.D.J., G.B., M.D., J.D., C.D.P. and H.T.C. Human genetics was carried out by P.J.N., A.J.M., C.R.-L., T.J.V., E.P. and T.J.A., and the manuscript was written by T.J.A., H.T.C., T.J.V. and J.M.

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Author notes

  1. Rong Dong, Timothy J. Vyse and Penny J. Norsworthy: *These authors contributed equally to this work

Authors and Affiliations

  1. Physiological Genomics and Medicine Group, MRC Clinical Sciences Centre, Sections of Imperial College, W12 0NN, London, UK
    Timothy J. Aitman, Rong Dong, Penny J. Norsworthy, Michelle D. Johnson, Jonathan Mangion, Cheri Roberton-Lowe, Amy J. Marshall, Enrico Petretto, Matthew D. Hodges, Sheetal G. Patel, Kelly Sheehan-Rooney, Mark Duda & Paul R. Cook
  2. Rheumatology and Imperial College, W12 0NN, London, UK
    Timothy J. Vyse & Cheri Roberton-Lowe
  3. Renal Medicine, Imperial College, W12 0NN, London, UK
    Jennifer Smith, Gurjeet Bhangal, Mark Duda, Paul R. Cook, David J. Evans, Jan Domin & Charles D. Pusey
  4. Wellcome Trust Centre for Human Genetics, OX3 7BN, Oxford, UK
    Jonathan Flint
  5. Department of Histopathology, Imperial College, W12 0NN, London, UK
    Joseph J. Boyle & H. Terence Cook

Authors

  1. Timothy J. Aitman
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  2. Rong Dong
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  3. Timothy J. Vyse
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  4. Penny J. Norsworthy
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  5. Michelle D. Johnson
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  6. Jennifer Smith
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  7. Jonathan Mangion
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  8. Cheri Roberton-Lowe
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  9. Amy J. Marshall
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  10. Enrico Petretto
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  11. Matthew D. Hodges
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  12. Gurjeet Bhangal
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  13. Sheetal G. Patel
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  14. Kelly Sheehan-Rooney
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  15. Mark Duda
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  16. Paul R. Cook
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  17. David J. Evans
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  18. Jan Domin
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  19. Jonathan Flint
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  20. Joseph J. Boyle
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  21. Charles D. Pusey
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  22. H. Terence Cook
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Corresponding authors

Correspondence toTimothy J. Aitman or H. Terence Cook.

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Competing interests

The sequence of Fcgr3-rs exon 5 has been deposited in GenBank under accession number AY561710. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figures and Legends

This file contains Supplementary Figures 1–4. Supplementary Figure 1 details the distribution of phenotypes in rat parental strains, and in F1 and F2 animals. Supplementary Figure 2 details the results of the rat Fcgr3 clonotype analysis. Supplementary Figure 3 details the surface expression analysis of Fcgr3 isoforms. Supplementary Figure 4 details the copy number quantification data for human FCGR3B and the control gene CD36. (DOC 640 kb)

Supplementary Table

This contains the results from the logistic regression analysis carried out in patients with lupus nephritis. (DOC 50 kb)

Supplementary Methods

This contains detailed methods and resources used in the rodent and human studies to complement the brief Methods section of the main text. (DOC 61 kb)

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Aitman, T., Dong, R., Vyse, T. et al. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans.Nature 439, 851–855 (2006). https://doi.org/10.1038/nature04489

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Editorial Summary

Too much of a good thing?

Glomerulonephritis is a kidney inflammation that occurs alone or as part of other conditions, including the autoimmune disorder lupus. A novel mutation has now been identified as the cause of the disease in a rat model. The mutation affects the Fcgr3 immunoglobulin receptor, but it does not produce a defective receptor. Rather, too many copies of an otherwise normal gene are produced. A similar gene-number defect was then detected in a subset of human systemic lupus erythematosus patients with a kidney inflammation. In these patients an equivalent receptor gene, FCGR3B, is present at a low copy number. Disease seems to result when copy number is altered in either direction, so receptor levels must need to be very finely tuned.

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