Genetic Association between Low Expression Phenotype of CD62L (L-selectin) in Peripheral CD4+ T cells and the thid (T-helper Immunodeficiency) phenotype in the LEC Rat.

Jung, Cha-Gyun; Miyamoto, Tomomi; Tsumagari, Takashi; Agui, Takashi

doi:10.1538/expanim.50.337

Cited by 3 publications

(2 citation statements)

References 12 publications

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“…We noticed that the phenotype of Gasp Ϫ/Ϫ mice was quite similar to thid (LEC) mutant rat (16). Those reports showed reduced numbers of CD4-SP cells, but not CD8-SP cells in lymph nodes (16), and lower expression of CD62L in CD4-SP cells (17), which are exactly the same phenotypes as Gasp Ϫ/Ϫ mice. The responsible gene for thid mutation was recently reported as PTPRK (protein tyrosine phosphatase receptor K) (18,19), and the gene is only 100 Kb apart from the Gasp gene locus.…”

Section: Resultssupporting

confidence: 54%

Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes

Patrick

Oda²,

Hayakawa³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

106

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T cells develop in the thymus through positive and negative selection, which are responsible for shaping the T cell receptor (TCR) repertoire. To elucidate the molecular mechanisms involved in selection remains an area of intense interest. Here, we identified and characterized a gene product Gasp (Grb2-associating protein, also called Themis) that is critically required for positive selection. Gasp is a cytosolic protein with no known functional motifs that is expressed only in T cells, especially immature CD4/CD8 double positive (DP) thymocytes. In the absence of Gasp, differentiation of both CD4 and CD8 single positive cells in the thymus was severely inhibited, whereas all other TCRinduced events such as ␤-selection, negative selection, peripheral activation, and homeostatic proliferation were unaffected. We found that Gasp constitutively associates with Grb2 via its N-terminal Src homology 3 domain, suggesting that Gasp acts as a thymocytespecific adaptor for Grb2 or regulates Ras signaling in DP thymocytes. Collectively, we have described a gene called Gasp that is critical for positive selection. (2). The fate of individual DP thymocytes is determined by the strength of affinity and longevity of interaction between their TCR and peptide:MHC ligand (3). Although it is known that strong TCR/ligand interaction leads to negative selection and weak association results in positive selection (4), how this quantitative difference of TCR interaction can be converted to the qualitative difference is not known. Therefore, it is important to investigate the difference in molecular mechanisms of positive and negative selection.

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Section: Resultssupporting

confidence: 54%

Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes

Patrick

Oda²,

Hayakawa³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

106

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“…These are apparently unrelated to Atp7b deficiency and because of deletions in Ptprk (encoding protein tyrosine phosphatase kappa) and Themis. There is maturational arrest of CD4+ cells in the thymus, resulting in Thelper immunodeficiency (thid) with unknown implications on the hepatic phenotype (Chai et al 1996;Jung et al 2001;Asano et al 2007;Iwata et al 2010). Other features of the LEC rat limiting its use in modelling WD include the frequent occurrence of hepatocellular and cholangiocarcinoma.…”

Section: Limitationsmentioning

confidence: 99%

Animal models of Wilson disease

Reed

Lutsenko²,

Bandmann

2018

Journal of Neurochemistry

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Wilson disease (WD) is an autosomal recessive disorder of copper metabolism manifesting with hepatic, neurological and psychiatric symptoms. The limitations of the currently available therapy for WD (particularly in the management of neuropsychiatric disease), together with our limited understanding of key aspects of this illness (e.g. neurological vs. hepatic presentation) justify the ongoing need to study WD in suitable animal models. Four animal models of WD have been established: the Long-Evans Cinnamon rat, the toxic-milk mouse, the Atp7b knockout mouse and the Labrador retriever. The existing models of WD all show good similarity to human hepatic WD and have been helpful in developing an improved understanding of the human disease. As mammals, the mouse, rat and canine models also benefit from high homology to the human genome. However, important differences exist between these mammalian models and human disease, particularly the absence of a convincing neurological phenotype. This review will first provide an overview of our current knowledge of the orthologous genes encoding ATP7B and the closely related ATP7A protein in C. elegans, Drosophila and zebrafish (Danio rerio) and then summarise key characteristics of rodent and larger mammalian models of ATP7B-deficiency.

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A deletion mutation of the protein tyrosine phosphatase kappa (Ptprk) gene is responsible for T-helper immunodeficiency (thid) in the LEC rat

et al. 2007

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Bone marrow (BM)-derived T-cell progenitors differentiate into CD4 or CD8 single positive (SP) cells in the thymus. We have previously reported that a single autosomal mutation, thid, causes a defect in maturation of CD4 SP thymocytes and an abnormality of peripheral helper-T cells in the LEC rat. In this study, we attempted to identify a gene responsible for the thid mutation. We first performed genetic linkage analysis and mapped thid locus between Myb and D1Rat392 on Chr 1. In this region, we found a ~380 kb deletion from intron 3 of the Ptprk gene, which encodes a receptor-like protein tyrosine phosphatase type κ (RPTPκ), to intron 1 of RGD1560849 predicted gene in the LEC rat genome. Reconstitution with syngenic BM cells transduced Ptprk but not RGD1560849 predicted gene rescued development of CD4 SP cells in the LEC rat thymus. It is confirmed by this result that the Ptprk gene is responsible for the thid mutation in the LEC rat. Our results further suggest that RPTPκ plays a critical role in the development of CD4 SP cells in the thymus.

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Genetic Association between Low Expression Phenotype of CD62L (L-selectin) in Peripheral CD4+ T cells and the thid (T-helper Immunodeficiency) phenotype in the LEC Rat.

Cited by 3 publications

References 12 publications

Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes

Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes

Animal models of Wilson disease

A deletion mutation of the protein tyrosine phosphatase kappa (Ptprk) gene is responsible for T-helper immunodeficiency (thid) in the LEC rat

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