|Mutation Type||frame shift|
|Coordinate||78,481,834 bp (GRCm38)|
|Base Change||TAGTCA ⇒ TAGTCAGTCA (forward strand)|
|Gene Name||interleukin 2 receptor, beta chain|
|Synonym(s)||IL-15 receptor beta chain, CD122, IL-15Rbeta, IL15Rbeta, IL-2/15Rbeta, Il-2Rbeta|
|Chromosomal Location||78,479,256-78,495,271 bp (-)|
FUNCTION: The interleukin 2 receptor is composed of alpha and beta subunits. The beta subunit encoded by this gene is very homologous to the human beta subunit and also shows structural similarity to other cytokine receptors. [provided by RefSeq, Jul 2008]
PHENOTYPE: Homozygotes for a targeted null mutation exhibit spontaneous activation of T cells and differentiation of B cells, elevated immunoglobulins including autoantibodies causing hemolytic anemia, granulocytopoiesis, and death after 3 months of age. [provided by MGI curators]
|Amino Acid Change|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000086820 †] [ENSMUSP00000127006 †] † probably from a misspliced transcript|
|Predicted Effect||probably null|
|Predicted Effect||probably null|
|Meta Mutation Damage Score||0.9755|
|Is this an essential gene?||Probably nonessential (E-score: 0.102)|
|Candidate Explorer Status||CE: excellent candidate; Verification probability: 0.927; ML prob: 0.89; human score: 2.5|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Last Updated||2019-09-04 9:27 PM by Anne Murray|
|Record Created||2019-03-14 8:27 AM by Bruce Beutler|
The Moonpie phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R6666, some of which showed increased CD4 to CD8 T cell ratios (Figure 1), reduced frequencies of CD8+ T cells (Figure 2), CD8+ T cells in CD3+ T cells (Figure 3), central memory CD8 T cells in CD8 T cells (Figure 4), NK cells (Figure 5), and NK T cells (Figure 6) with concomitant increased frequencies of CD4+ T cells in CD3+ T cells (Figure 7), all in the peripheral blood. Some mice also showed reduced CD44 expression on peripheral blood CD8 T cells (Figure 8) and increased IgM expression on peripheral blood B cells (Figure 9).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 45 mutations. All of the above phenotypes were linked by continuous variable mapping to a mutation in Il2rb: a TGACTA ⇒ TGACTGACTA frameshift at base pair 78,481,834 (v38) on chromosome 15, or base pair 29,783 in the GenBank genomic region NC_000081 encoding Il2rb. The strongest association was found with an additive model of inheritance to the normalized NK cell frequency phenotype, wherein four variant homozygotes and nine heterozygous mice departed phenotypically from 16 homozygous reference mice with a P value of 4.607 x 10-13 (Figure 10).
The mutation corresponds to residue 1,406 in the mRNA sequence NM_008368 within exon 10 of 10 total exons.
The mutated nucleotide is indicated in red. The effect of the mutation at the cDNA and protein levels has not been examined, but the mutation is predicted to result in coding of a premature stop codon after amino acid 420 (the protein is normally 539 amino acids in length) in the CD122 protein.
|Illustration of Mutations in
Gene & Protein
Il2rb encodes CD122 (alternatively, IL2Rβ), the beta chain of the IL-2 receptor (1). The IL-2 receptor has three subunits: α, β (CD122), and γc. The receptors for IL-2, 4, 7, 9, and 15 have a common γ chain, and the receptors for IL-2 and IL-15 share the β chain (2). The β and γc subunits together form an intermediate affinity receptor (3). Upon co-expression of the α subunit, the receptor is converted to a high affinity receptor [PDB:2B5I; (4;5)].
CD122 is a single-pass transmembrane protein, with an extracellular N-terminus and a cytoplasmic C-terminus (Figure 11). Amino acids 1 to 26 are a signal peptide. IL2RB has a single fibronectin type-III domain (FN3; amino acids 135 to 235), a WSXWS motif (amino acids 221 to 225), and a box 1 motif (amino acids 281 to 289). CD122 is cleaved, which generates a 37-kDa fragment (termed 37βic) containing the C-terminal tail and transmembrane domains (6). The CD122 fragment is functional and associates with STAT5 to promote cell proliferation.
The Moonpie mutation is predicted to result in coding of a premature stop codon after amino acid 420 in the CD122 protein; Amino acid 420 is within an undefined region in the cytoplasmic C-terminal tail.
Please see the record flybase for more information about Il2rb.
IL-2/IL-15 receptor-associated signaling functions in antigen-driven T cell-expansion, and maintains peripheral T cell homeostasis as well as promotes the differentiation and function of NK cells and B cells. Stimulation of the IL-2 receptor (containing a γc subunit) results in activation of JAK3. Activated JAK3 phosphorylates the receptor cytoplasmic domains, creating phosphotyrosine ligands for the SH2 domains of STAT5. Once recruited to the receptor, STAT5 is also tyrosine phosphorylated by JAK3. Phosphorylated, activated STAT5 enters the nucleus and accumulates there to promote transcription.
Il2rb-deficient (Il2rb-/-) mice exhibited reduced numbers of regulatory T cells in the thymus and lymph nodes, enlarged spleens, increased sizes of spleen periarteriolar lymphoid sheaths, aberrant T cell responses to inflammatory cytokines, increased percentages of CD4 and CD8 T cells that express high levels of activation markers, reduced T cell proliferation, enlarged lymph nodes, increased levels of anti-DNA antibodies, and increased susceptibility to autoimmune hemolytic anemia (7;8). In addition, Il2rb-/- mice showed reduced numbers of double-positive T cells, B cells, and memory T cells; increased numbers of plasma cells, CD4+ T cells and CD8+ T cells in the thymus, erythroid progenitors in the blood, and neutrophils in the lymph nodes, and increased levels of IgE and IgG1 in the sera (8). Il2rb-/- mice also showed premature death, weight loss, slow movements, fuzzy hair, and poorly developed genitalia (8).
The phenotypes observed in the Moonpie mice mimics that of Il2rb-/- mice, indicating loss of CD122-associated function.
1) 94°C 2:00
The following sequence of 440 nucleotides is amplified (chromosome 15, - strand):
1 accaaccagg gctacttctt cttccatctg cccaatgcct tggagatcga atcctgccag
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Gnarra, J. R., Otani, H., Wang, M. G., McBride, O. W., Sharon, M., and Leonard, W. J. (1990) Human Interleukin 2 Receptor Beta-Chain Gene: Chromosomal Localization and Identification of 5' Regulatory Sequences. Proc Natl Acad Sci U S A. 87, 3440-3444.
2. Giri, J. G., Ahdieh, M., Eisenman, J., Shanebeck, K., Grabstein, K., Kumaki, S., Namen, A., Park, L. S., Cosman, D., and Anderson, D. (1994) Utilization of the Beta and Gamma Chains of the IL-2 Receptor by the Novel Cytokine IL-15. EMBO J. 13, 2822-2830.
3. Takeshita, T., Ohtani, K., Asao, H., Kumaki, S., Nakamura, M., and Sugamura, K. (1992) An Associated Molecule, p64, with IL-2 Receptor Beta Chain. its Possible Involvement in the Formation of the Functional Intermediate-Affinity IL-2 Receptor Complex. J Immunol. 148, 2154-2158.
4. Wang, X., Rickert, M., and Garcia, K. C. (2005) Structure of the Quaternary Complex of Interleukin-2 with its Alpha, Beta, and Gammac Receptors. Science. 310, 1159-1163.
5. Arima, N., Kamio, M., Okuma, M., Ju, G., and Uchiyama, T. (1991) The IL-2 Receptor Alpha-Chain Alters the Binding of IL-2 to the Beta-Chain. J Immunol. 147, 3396-3401.
6. Montes de Oca, P., Malarde, V., Proust, R., Dautry-Varsat, A., and Gesbert, F. (2010) Ectodomain Shedding of Interleukin-2 Receptor Beta and Generation of an Intracellular Functional Fragment. J Biol Chem. 285, 22050-22058.
7. Malek, T. R., Yu, A., Vincek, V., Scibelli, P., and Kong, L. (2002) CD4 Regulatory T Cells Prevent Lethal Autoimmunity in IL-2Rbeta-Deficient Mice. Implications for the Nonredundant Function of IL-2. Immunity. 17, 167-178.
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Jin Huk Choi, Xue Zhong, and Bruce Beutler|