FUNCTION: This gene encodes a member of the protein tyrosine kinase family. The encoded protein is essential for development of T lymphocytes and thymocytes, and functions in the initial step of T lymphocyte receptor-mediated signal transduction. A mutation in this gene causes chronic autoimmune arthritis, similar to rheumatoid arthritis in humans. Mice lacking this gene are deficient in alpha-beta T lymphocytes in the thymus. In humans, mutations in this gene cause selective T-cell defect, a severe combined immunodeficiency disease characterized by a selective absence of CD8-positive T lymphocytes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014] PHENOTYPE: Mutant mice show T cell defects. Null mutants lack alpha-beta T cells in the thymus and have fewer T cells in dendritic and intestinal epithelium. Spontaneous and knock-in missense mutations affect T cell receptor signaling, one of the former resulting in severe chronic arthritis. [provided by MGI curators]
The mrtless (mrt) phenotype was identified in a flow cytometry screen of blood from N-ethyl-N-nitrosourea (ENU)-mutagenized mice for mutations affecting the circulating proportions of memory and naïve T cells (1). Homozygous mrtless mice display an almost complete arrest of T cell development at the CD4+CD8+ double positive (DP) stage resulting in very few peripheral T cells. Cluster of differentiation 5 (CD5) and CD69 are upregulated on T cells in response to T cell activation. A comparison of CD5 and CD69 expression in Zap70mrt/mrt and homozygous null Zap70−/− animals established that Zap70mrt/mrt thymocytes have greater responsiveness to TCR stimulation than thymocytes with no ZAP-70 (Figure 1).
Please see the record for murdockfor more information about the Zap70mrt allele.
Nature of Mutation
The mrtless mutation was mapped to Chromosome 1, and corresponds to a T to C transition at position 1601 of the Zap70 transcript, in exon 11 of 13 total exons.
The mutated nucleotide is indicated in red lettering and causes a tryptophan to arginine change at amino acid 504 of the encoded protein.
Figure 2. Structure of ZAP-70. Mouse Zap-70 is a 618 amino acid protein tyrosine kinasen (PTK) that consists of two N-terminal Src-homology 2 (SH2) domains and a C-terminal kinase domain. The SH2 domains are connected by a linker known as interdomain A (IDA), while the region between the second SH2 and catalytic domains is known as interdomain B (IDB). The aspartic acid (D) of the residue 459 is the proton acceptor during the catalytic cycle. Several tyrosine (Y) residues located within interdomain B are phosphorylated following TCR stimulation (291, 314, and 318). Phosphorylation of Tyr 492 is required for ZAP-70 activation, while Tyr 491 phosphorylation negatively regulates ZAP-70 function. The mrtless mutation causes a tryptophan to arginine change at amino acid 504. The 3D structure is human ZAP70. UCSF Chimera structure based on PDB 2OZO. This image is interactive. Other mutations found in ZAP-70 are noted in red. Click on the mutations for more specific information. Click on the 3D structure to view it rotate.
The mrtless mutation results in a tryptophan to arginine substitution of a conserved residue in the activation loop within the catalytic site of the kinase domain at amino acid 504 (Figure 2). The aberrant protein is expressed at 25% of wild-type levels (1).
Please see the record for murdock for more information about Zap70.
Primers cannot be located by automatic search.
Genotyping protocols are from the Australian PhenomeBank.