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.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Ohno, S., Wolf, U. & Atkin, N. B. Evolution from fish to mammals by gene duplication. Hereditas 59, 169–187 (1968)
    Article CAS Google Scholar
  2. Glazier, A. M., Nadeau, J. H. & Aitman, T. J. Finding genes that underlie complex traits. Science 298, 2345–2349 (2002)
    Article ADS CAS Google Scholar
  3. Eichler, E. E. & Sankoff, D. Structural dynamics of eukaryotic chromosome evolution. Science 301, 793–797 (2003)
    Article ADS CAS Google Scholar
  4. Stankiewicz, P. & Lupski, J. R. Genome architecture, rearrangements and genomic disorders. Trends Genet. 18, 74–82 (2002)
    Article CAS Google Scholar
  5. Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004)
    Article ADS CAS Google Scholar
  6. Kawasaki, K., Yaoita, E., Yamamoto, T. & Kihara, I. Depletion of CD8 positive cells in nephrotoxic serum nephritis of WKY rats. Kidney Int. 41, 1517–1526 (1992)
    Article CAS Google Scholar
  7. Sado, Y., Naito, I., Akita, M. & Okigaki, T. Strain specific responses of inbred rats on the severity of experimental autoimmune glomerulonephritis. J. Clin. Lab. Immunol. 19, 193–199 (1986)
    CAS PubMed Google Scholar
  8. Isome, M. et al. Important role for macrophages in induction of crescentic anti-GBM glomerulonephritis in WKY rats. Nephrol. Dial. Transplant. 19, 2997–3004 (2004)
    Article Google Scholar
  9. Ferrario, F. & Pia Rastaldi, M. in Rapidly Progressive Glomerulonephritis (eds Pusey, C. D. & Rees, A. J.) 59–107 (Oxford Univ. Press, Oxford, 1998)
    Google Scholar
  10. Yamori, Y. in Handbook of Hypertension Vol. 4 Experimental and Genetic Models of Hypertension (ed. de Jong, W.) 224–239 (Elsevier, New York, 1984)
    Google Scholar
  11. Roberton, C. A. Fine Mapping Candidate Gene Families in Human Systemic Lupus Erythematosus. Thesis, Univ. London (2003)
    Google Scholar
  12. Karassa, F. B., Trikalinos, T. A. & Ioannidis, J. P. Role of the Fcγ receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis. Arthritis Rheum. 46, 1563–1571 (2002)
    Article CAS Google Scholar
  13. Edberg, J. C. et al. Genetic linkage and association of Fcγ receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus. Arthritis Rheum. 46, 2132–2140 (2002)
    Article CAS Google Scholar
  14. Ravetch, J. V. Fc receptors: rubor redux. Cell 78, 553–560 (1994)
    Article CAS Google Scholar
  15. Takai, T. Roles of Fc receptors in autoimmunity. Nature Rev. Immunol. 2, 580–592 (2002)
    Article CAS Google Scholar
  16. Kurosaki, T. & Ravetch, J. V. A single amino acid in the glycosyl phosphatidylinositol attachment domain determines the membrane topology of FcγRIII. Nature 342, 805–807 (1989)
    Article ADS CAS Google Scholar
  17. Coxon, A. et al. FcγRIII mediates neutrophil recruitment to immune complexes. A mechanism for neutrophil accumulation in immune-mediated inflammation. Immunity 14, 693–704 (2001)
    Article CAS Google Scholar
  18. Aitman, T. J. et al. Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. Nature Genet. 21, 76–83 (1999)
    Article CAS Google Scholar
  19. Pravenec, M. et al. Transgenic rescue of defective Cd36 ameliorates insulin resistance in spontaneously hypertensive rats. Nature Genet. 27, 156–158 (2001)
    Article CAS Google Scholar
  20. Gonzalez, E. et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307, 1434–1440 (2005)
    Article ADS CAS Google Scholar
  21. Farber, D. L. et al. Rat class III Fcγ receptor isoforms differ in IgG subclass-binding specificity and fail to associate productively with rat CD3ζ. J. Immunol. 150, 4364–4375 (1993)
    CAS PubMed Google Scholar
  22. Clark, M. R., Liu, L., Clarkson, S. B., Ory, P. A. & Goldstein, I. M. An abnormality of the gene that encodes neutrophil Fc receptor III in a patient with systemic lupus erythematosus. J. Clin. Invest. 86, 341–346 (1990)
    Article CAS Google Scholar
  23. Koene, H. R., Kleijer, M., Roos, D., de Haas, M. & Von dem Borne, A. E. FcγRIIIB gene duplication: evidence for presence and expression of three distinct FcγRIIIB genes in NA(1 +,2 + )SH(+ ) individuals. Blood 91, 673–679 (1998)
    CAS PubMed Google Scholar
  24. Gittinger, F. S., Schindler-Wuepper, L., Kissel, K. & Bux, J. Quantitative determination of Fcγ receptor genes by means of fluorescence-based real-time polymerase chain reaction. Tissue Antigens 60, 64–70 (2002)
    Article CAS Google Scholar
  25. Bhan, A. K., Schneeberger, E. E., Collins, A. B. & McCluskey, R. T. Evidence for a pathogenic role of a cell-mediated immune mechanism in experimental glomerulonephritis. J. Exp. Med. 148, 246–260 (1978)
    Article CAS Google Scholar
  26. Cook, H. T. et al. Interleukin-4 ameliorates crescentic glomerulonephritis in Wistar Kyoto rats. Kidney Int. 55, 1319–1326 (1999)
    Article CAS Google Scholar
  27. Boyle, J. J. Human macrophages kill human mesangial cells by Fas-L-induced apoptosis when triggered by antibody via CD16. Clin. Exp. Immunol. 137, 529–537 (2004)
    Article CAS Google Scholar
  28. Kim, M. K. et al. Fcγ receptor transmembrane domains: role in cell surface expression, gamma chain interaction, and phagocytosis. Blood 101, 4479–4484 (2003)
    Article CAS Google Scholar
  29. Russell, A. I. et al. Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus. Hum. Mol. Genet. 13, 137–147 (2004)
    Article CAS Google Scholar
  30. Tan, E. M. et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 25, 1271–1277 (1982)
    Article CAS Google Scholar

Download references

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.

Author information

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

Corresponding authors

Correspondence toTimothy J. Aitman or H. Terence Cook.

Ethics declarations

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)

Rights and permissions

About this article

Cite this article

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

Download citation

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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.

Associated content

Copies count

Nature News & Views 15 Feb 2006