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|Coordinate||140,876,495 bp (GRCm38)|
|Base Change||G ⇒ A (forward strand)|
|Gene Name||caspase recruitment domain family, member 11|
|Synonym(s)||CARMA1, BIMP3, 2410011D02Rik, 0610008L17Rik|
|Chromosomal Location||140,872,990-141,000,582 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene belongs to the membrane-associated guanylate kinase (MAGUK) family, a class of proteins that functions as molecular scaffolds for the assembly of multiprotein complexes at specialized regions of the plasma membrane. This protein is also a member of the CARD protein family, which is defined by carrying a characteristic caspase-associated recruitment domain (CARD). This protein has a domain structure similar to that of CARD14 protein. The CARD domains of both proteins have been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. When expressed in cells, this protein activated NF-kappaB and induced the phosphorylation of BCL10. [provided by RefSeq, Jul 2008]
PHENOTYPE: Mice homozygous for a targeted null mutation exhibit defects in antigen receptor signalling in both T and B lymphocytes. [provided by MGI curators]
|Amino Acid Change||Arginine changed to Stop codon|
|Institutional Source||Beutler Lab|
|Gene Model||not available|
AA Change: R1016*
|Predicted Effect||probably null|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Dominant|
|Local Stock||Live Mice, Sperm|
|Last Updated||2017-09-08 4:04 PM by Diantha La Vine|
|Record Created||2011-01-30 2:13 PM by Carrie N. Arnold|
|Other Mutations in This Stock||
Stock #: V7732 Run Code: HSQ01006
Coding Region Coverage: 10x: 94.9% 20x: 90.3%
Validation Efficiency: 25/26
The May phenotype was identified among ENU-mutagenized G3 mice in a screen for mutations impair T-independent B cell responses. May mice mice have low T-independent IgM responses 5 days after immunization with NP-Ficoll (Figure 1, left), but normal T-dependent IgG responses 14 days after immunization with a recombinant SFV vector encoding the model antigen, β-galactosidase (βGal) (Figure 1, right). May B cells express high surface levels of IgM.
|Nature of Mutation|
The May strain was regenerated by intracytoplasmic sperm injection (ICSI) of cryopreserved sperm from an affected homozygote into C57BL/6J oocytes. Whole exome HiSeq sequencing of one of the resulting mice, an affected female, identified 26 mutations. Based on initial genotyping of the 26 mutation sites in one affected and three unaffected mice, five candidate genes (Ggh, 1810074P20Rik, Card11, Fanca, Rps24) were identified because they were homozygous for the reference sequence in all unaffected mice and heterozygous for the mutant allele in the affected mouse. Subsequent analysis of nine additional affected mice and two unaffected mice provided strongest support for a Card11 mutation as causal for the May phenotype; bulk segregation analysis (BSA) also indicated that the mutation in Card11 was causative. The mutation is a C to T transition at base pair 140876495 (v38) on Chromosome 5 in the GenBank genomic region NC_000071 encoding Card11. The mutation corresponds to residue 3367 in the mRNA sequence NM_175362 within exon 23 of 25 total exons. Phenotypic inheritance pattern suggests that the May mutation is semi-dominant or dominant.
The mutated nucleotide is indicated in red. The mutation results in an arginine (R) to premature stop codon substitution at amino acid 1016.
The May mutation is an arginine to premature stop codon subsitition at position 1016 of CARMA1, the protein encoded by Card11. The CARMA1 protein has a membrane-associated guanylate kinase (MAGUK) domain at the C-terminus. MAGUK family proteins contain 3 modular protein interaction domains, of which the hallmark is an approximately 300 amino acid region with homology to yeast guanylate kinase (GUK), but which is catalytically inactive. In addition, up to three PDZ domains and an SH3 domain are always present in tandem with the guanylate kinase domain. The May mutation is within the GUK subdomain (amino acids 954-1142) (1;2). Protein expression in the May mice has not been examined.
Please see the record for king for more information about Card11.
The phenotype of the May mice is similar to those observed in other CARMA1 mutants (3-6). For example, homozygous unmodulated mice displayed impaired IgM and IgG3 responses to immunization with DNP-Ficoll (7). The IgM and IgG responses to the T-dependent antigen chicken γ globulin were reduced in unmodulated mice (7); this phenotype has not been tested in May animals. Taken together, these data strongly suggest that the May mutation causes a loss of function of the CARMA1 protein. As the May mutation is a late stop codon, it is possible that the protein product is mostly intact and capable of engaging its interaction partners in the CARMA1/BCL10/MALT1 complex, but dominantly inhibits complex function. Upon T cell receptor-mediated activation of the T cell, the CARMA1/BCL10/MALT1 complex is recruited to lipid rafts of the immunological synapse and activates the IKK complex, leading to the degradation of IκB and the subsequent activation of NF-κB (2;3;8-11). The CARMA1/BCL10/MALT1 complex functions similarly in B cells to activate NF-κB in response to BCR engagement (12).
|Primers||Primers cannot be located by automatic search.|
May genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide transition.
May(F): 5’- TGCATGGTCTGGCAGAGCAATC -3’
May(R): 5’- ATGACCCAGTGCCTCACAGAGATG -3’
May_seq(F): 5’- GCCTCACAGAGATGGTTGG -3’
1) 94°C 2:00
2) 94°C 0:30
3) 55°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 40X
6) 72°C 10:00
7) 4°C ∞
The following sequence of 404 nucleotides (from Genbank genomic region NC_000071 for linear DNA sequence of Card11) is amplified:
123864 tgcatgg tctggcagag caatcatgaa cttgacccca
123901 ctcccaggga gcttccctat ctagtagaga agatgatgtt ccatttaacc aaagtgggaa
123961 agaaccagat gaatatcaaa ttatgtggca cttaggaggg acagataggg cctggaagag
124021 acaacccacc acaaatagca cttgccaccc tgggcactaa ctcccctctc ttcagatatt
124081 gtcacaagag atgagttcct ccgaaagcag aagacagaga ccatcatcta ctcccgggaa
124141 aagaacccca acacctttga atgcatcgtc cctgccaaca ttgaggctgt ggcagccaag
124201 gtgagagacc ctgggtactg gccagactaa ggccctaccc aaccatctct gtgaggcact
Primer binding sites are underlined and the sequencing primer is highlighted; the mutated C is shown in red text.
1. Bertin, J., Wang, L., Guo, Y., Jacobson, M. D., Poyet, J. L., Srinivasula, S. M., Merriam, S., DiStefano, P. S., and Alnemri, E. S. (2001) CARD11 and CARD14 are Novel Caspase Recruitment Domain (CARD)/membrane-Associated Guanylate Kinase (MAGUK) Family Members that Interact with BCL10 and Activate NF-Kappa B. J Biol Chem. 276, 11877-11882.
2. Gaide, O., Martinon, F., Micheau, O., Bonnet, D., Thome, M., and Tschopp, J. (2001) Carma1, a CARD-Containing Binding Partner of Bcl10, Induces Bcl10 Phosphorylation and NF-kappaB Activation. FEBS Lett. 496, 121-127.
3. Egawa, T., Albrecht, B., Favier, B., Sunshine, M. J., Mirchandani, K., O'Brien, W., Thome, M., and Littman, D. R. (2003) Requirement for CARMA1 in Antigen Receptor-Induced NF-Kappa B Activation and Lymphocyte Proliferation. Curr Biol. 13, 1252-1258.
4. Hara, H., Wada, T., Bakal, C., Kozieradzki, I., Suzuki, S., Suzuki, N., Nghiem, M., Griffiths, E. K., Krawczyk, C., Bauer, B., D'Acquisto, F., Ghosh, S., Yeh, W. C., Baier, G., Rottapel, R., and Penninger, J. M. (2003) The MAGUK Family Protein CARD11 is Essential for Lymphocyte Activation. Immunity. 18, 763-775.
5. Barnes, M. J., Krebs, P., Harris, N., Eidenschenk, C., Gonzalez-Quintial, R., Arnold, C. N., Crozat, K., Sovath, S., Moresco, E. M., Theofilopoulos, A. N., Beutler, B., and Hoebe, K. (2009) Commitment to the Regulatory T Cell Lineage Requires CARMA1 in the Thymus but Not in the Periphery. PLoS Biol. 7, e51.
6. Newton, K., and Dixit, V. M. (2003) Mice Lacking the CARD of CARMA1 Exhibit Defective B Lymphocyte Development and Impaired Proliferation of their B and T Lymphocytes. Curr Biol. 13, 1247-1251.
7. Jun, J. E., Wilson, L. E., Vinuesa, C. G., Lesage, S., Blery, M., Miosge, L. A., Cook, M. C., Kucharska, E. M., Hara, H., Penninger, J. M., Domashenz, H., Hong, N. A., Glynne, R. J., Nelms, K. A., and Goodnow, C. C. (2003) Identifying the MAGUK Protein Carma-1 as a Central Regulator of Humoral Immune Responses and Atopy by Genome-Wide Mouse Mutagenesis. Immunity. 18, 751-762.
8. Gaide, O., Favier, B., Legler, D. F., Bonnet, D., Brissoni, B., Valitutti, S., Bron, C., Tschopp, J., and Thome, M. (2002) CARMA1 is a Critical Lipid Raft-Associated Regulator of TCR-Induced NF-Kappa B Activation. Nat Immunol. 3, 836-843.
9. Che, T., You, Y., Wang, D., Tanner, M. J., Dixit, V. M., and Lin, X. (2004) MALT1/paracaspase is a Signaling Component Downstream of CARMA1 and Mediates T Cell Receptor-Induced NF-kappaB Activation. J Biol Chem. 279, 15870-15876.
10. Wang, D., You, Y., Case, S. M., McAllister-Lucas, L. M., Wang, L., DiStefano, P. S., Nunez, G., Bertin, J., and Lin, X. (2002) A Requirement for CARMA1 in TCR-Induced NF-Kappa B Activation. Nat Immunol. 3, 830-835.
11. Pomerantz, J. L., Denny, E. M., and Baltimore, D. (2002) CARD11 Mediates Factor-Specific Activation of NF-kappaB by the T Cell Receptor Complex. EMBO J. 21, 5184-5194.
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine, Peter Jurek|
|Authors||Carrie Arnold and Elaine Pirie|
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