Nature 439, 851-855 (16 February 2006) | doi:10.1038/nature04489

Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans

Timothy J. Aitman1, Rong Dong1,6, Timothy J. Vyse2,6, Penny J. Norsworthy1,6, Michelle D. Johnson1, Jennifer Smith3, Jonathan Mangion1, Cheri Roberton-Lowe1,2, Amy J. Marshall1, Enrico Petretto1, Matthew D. Hodges1, Gurjeet Bhangal3, Sheetal G. Patel1, Kelly Sheehan-Rooney1, Mark Duda1,3, Paul R. Cook1,3, David J. Evans3, Jan Domin3, Jonathan Flint4, Joseph J. Boyle5, Charles D. Pusey3 and H. Terence Cook5

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.

  1. Physiological Genomics and Medicine Group, MRC Clinical Sciences Centre, and Sections of
  2. Rheumatology and
  3. Renal Medicine, Imperial College, London W12 0NN, UK
  4. Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK
  5. Department of Histopathology, Imperial College, London W12 0NN, UK
  6. *These authors contributed equally to this work

Correspondence to: Timothy J. Aitman1H. Terence Cook5 Correspondence and requests for materials should be addressed to T.J.A. (Email: t.aitman@csc.mrc.ac.uk) or H.T.C. (Email: t.h.cook@imperial.ac.uk). The sequence of Fcgr3-rs exon 5 has been deposited in GenBank under accession number AY561710.

Received 3 August 2005; Accepted 22 November 2005


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