RGD Reference Report - Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. - Rat Genome Database

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

Authors: Aitman, TJ  Dong, R  Vyse, TJ  Norsworthy, PJ  Johnson, MD  Smith, J  Mangion, J  Roberton-Lowe, C  Marshall, AJ  Petretto, E  Hodges, MD  Bhangal, G  Patel, SG  Sheehan-Rooney, K  Duda, M  Cook, PR  Evans, DJ  Domin, J  Flint, J  Boyle, JJ  Pusey, CD  Cook, HT 
Citation: Aitman TJ, etal., Nature. 2006 Feb 16;439(7078):851-5.
RGD ID: 2293335
Pubmed: PMID:16482158   (View Abstract at PubMed)
DOI: DOI:10.1038/nature04489   (Journal Full-text)

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 genetics. 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 variation. 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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Biological Process

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Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
glomerular crescent susceptibilityIAGPanti-glomerular basement membrane antibody2293335 RGD 
glomerulonephritis susceptibilityIDA 2293335; 2293335 RGD 
glomerulonephritis  IDA 2293335; 2293335; 2293335; 2293335; 2293335 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Fcgr2a  (Fc gamma receptor 2A)

Genes (Mus musculus)
Fcgr3  (Fc receptor, IgG, low affinity III)

Genes (Homo sapiens)
FCGR2A  (Fc gamma receptor IIa)

QTLs
Glom15  (Glomerulus QTL 15)
Glom16  (Glomerulus QTL 16)
Glom22  (Glomerulus QTL 22)
Glom23  (Glomerulus QTL 23)
Glom24  (Glomerulus QTL 24)
Glom25  (Glomerulus QTL 25)
Glom26  (Glomerulus QTL 26)

Strains
LEW/NHsd  (NA)
WKY/NCrl  (NA)


Additional Information