RGD Reference Report - A spontaneous mutation of the rat Themis gene leads to impaired function of regulatory T cells linked to inflammatory bowel disease. - Rat Genome Database

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A spontaneous mutation of the rat Themis gene leads to impaired function of regulatory T cells linked to inflammatory bowel disease.

Authors: Chabod, Marianne  Pedros, Christophe  Lamouroux, Lucille  Colacios, Céline  Bernard, Isabelle  Lagrange, Dominique  Balz-Hara, Daniela  Mosnier, Jean-Francois  Laboisse, Christian  Vergnolle, Nathalie  Andreoletti, Olivier  Roth, Marie-Paule  Liblau, Roland  Fournié, Gilbert J  Saoudi, Abdelhadi  Dejean, Anne S 
Citation: Chabod M, etal., PLoS Genet. 2012 Jan;8(1):e1002461. doi: 10.1371/journal.pgen.1002461. Epub 2012 Jan 19.
RGD ID: 38599149
Pubmed: PMID:22275874   (View Abstract at PubMed)
PMCID: PMC3261907   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pgen.1002461   (Journal Full-text)

Spontaneous or chemically induced germline mutations, which lead to Mendelian phenotypes, are powerful tools to discover new genes and their functions. Here, we report an autosomal recessive mutation that occurred spontaneously in a Brown-Norway (BN) rat colony and was identified as causing marked T cell lymphopenia. This mutation was stabilized in a new rat strain, named BN(m) for "BN mutated." In BN(m) rats, we found that the T cell lymphopenia originated in the thymus, was intrinsic to CD4 T lymphocytes, and was associated with the development of an inflammatory bowel disease. Furthermore, we demonstrate that the suppressive activity of both peripheral and thymic CD4(+) CD25(bright) regulatory T cells (Treg) is defective in BN(m) rats. Complementation of mutant animals with BN Treg decreases disease incidence and severity, thus suggesting that the impaired Treg function is involved in the development of inflammatory bowel disease in BN(m) rats. Moreover, the cytokine profile of effector CD4 T cells is skewed toward Th2 and Th17 phenotypes in BN(m) rats. Linkage analysis and genetic dissection of the CD4 T cell lymphopenia in rats issued from BN(m)×DA crosses allowed the localization of the mutation on chromosome 1, within a 1.5 megabase interval. Gene expression and sequencing studies identified a frameshift mutation caused by a four-nucleotide insertion in the Themis gene, leading to its disruption. This result is the first to link Themis to the suppressive function of Treg and to suggest that, in Themis-deficient animals, defect of this function is involved in intestinal inflammation. Thus, this study highlights the importance of Themis as a new target gene that could participate in the pathogenesis of immune diseases characterized by chronic inflammation resulting from a defect in the Treg compartment.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
BN-Themism1AdejRatinflammatory bowel disease  IAGP  RGD 
THEMISHumaninflammatory bowel disease  ISOThemis (Rattus norvegicus)DNA:frameshift mutation:RGD 
ThemisRatinflammatory bowel disease  IAGP DNA:frameshift mutation:RGD 
ThemisMouseinflammatory bowel disease  ISOThemis (Rattus norvegicus)DNA:frameshift mutation:RGD 
Themism1AdejRatinflammatory bowel disease  IAGP  RGD 
BN-Themism1AdejRatT-Lymphocytopenia  IAGP  RGD 
THEMISHumanT-Lymphocytopenia  ISOThemis (Rattus norvegicus)DNA:frameshift mutation:RGD 
ThemisRatT-Lymphocytopenia  IAGP DNA:frameshift mutation:RGD 
ThemisMouseT-Lymphocytopenia  ISOThemis (Rattus norvegicus)DNA:frameshift mutation:RGD 
Themism1AdejRatT-Lymphocytopenia  IAGP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
BN-Themism1AdejRatabnormal duodenum morphology  IAGP compared to BNRGD 
ThemisRatabnormal duodenum morphology  IAGP DNA:frameshift mutation:RGD 
Themism1AdejRatabnormal duodenum morphology  IAGP compared to BNRGD 
BN-Themism1AdejRatabnormal ileum morphology  IAGP compared to BNRGD 
ThemisRatabnormal ileum morphology  IAGP DNA:frameshift mutation:RGD 
Themism1AdejRatabnormal ileum morphology  IAGP compared to BNRGD 
BN-Themism1AdejRatabnormal jejunum morphology  IAGP compared to BNRGD 
ThemisRatabnormal jejunum morphology  IAGP DNA:frameshift mutation:RGD 
Themism1AdejRatabnormal jejunum morphology  IAGP compared to BNRGD 
BN-Themism1AdejRatdecreased colon length  IAGP compared to BNRGD 
ThemisRatdecreased colon length  IAGP DNA:frameshift mutation:RGD 
Themism1AdejRatdecreased colon length  IAGP compared to BNRGD 
BN-Themism1AdejRatdecreased interferon-gamma secretion inducedIAGPanti-T cell receptor antibodycompared to BNRGD 
ThemisRatdecreased interferon-gamma secretion  IAGP DNA:frameshift mutation:RGD 
Themism1AdejRatdecreased interferon-gamma secretion  IAGP compared to BNRGD 
BN-Themism1AdejRatdecreased small intestine length  IAGP compared to BNRGD 
ThemisRatdecreased small intestine length  IAGP DNA:frameshift mutation:RGD 
Themism1AdejRatdecreased small intestine length  IAGP compared to BNRGD 
BN-Themism1AdejRatincreased interleukin-10 secretion inducedIAGPanti-T cell receptor antibodycompared to BNRGD 
ThemisRatincreased interleukin-10 secretion  IAGP DNA:frameshift mutation:RGD 
Themism1AdejRatincreased interleukin-10 secretion  IAGP compared to BNRGD 
BN-Themism1AdejRatincreased interleukin-17 secretion inducedIAGPanti-T cell receptor antibodycompared to BNRGD 
ThemisRatincreased interleukin-17 secretion  IAGP DNA:frameshift mutation:RGD 
Themism1AdejRatincreased interleukin-17 secretion  IAGP compared to BNRGD 
BN-Themism1AdejRatincreased interleukin-4 secretion inducedIAGPanti-T cell receptor antibodycompared to BNRGD 
ThemisRatincreased interleukin-4 secretion  IAGP DNA:frameshift mutation:RGD 
Themism1AdejRatincreased interleukin-4 secretion  IAGP compared to BNRGD 
BN-Themism1AdejRatincreased T cell proliferation inducedIAGPanti-T cell receptor antibodycompared to BNRGD 
ThemisRatincreased T cell proliferation  IAGP DNA:frameshift mutation:RGD 
Themism1AdejRatincreased T cell proliferation  IAGP compared to BNRGD 
Objects Annotated

Genes (Rattus norvegicus)
Themis  (thymocyte selection associated)
Themism1Adej  (thymocyte selection associated; mutant1, Adej)

Genes (Mus musculus)
Themis  (thymocyte selection associated)

Genes (Homo sapiens)
THEMIS  (thymocyte selection associated)

BN-Themism1Adej  (NA)

Additional Information