|List [record 53 of 0]|
|Mutation Type||critical splice donor site (2 bp from exon)|
|Coordinate||65,462,915 bp (GRCm38)|
|Base Change||T ⇒ C (forward strand)|
|Gene Name||MALT1 paracaspase|
|Chromosomal Location||65,430,962-65,478,823 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene has been found to be recurrently rearranged in chromosomal translocation with two other genes - baculoviral IAP repeat-containing protein 3 (also known as apoptosis inhibitor 2) and immunoglobulin heavy chain locus - in mucosa-associated lymphoid tissue lymphomas. The protein encoded by this gene may play a role in NF-kappaB activation. Two alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]
PHENOTYPE: Homozygous inactivation of this gene disrupts normal B cell development and leads to impaired cytokine production and T cell and B cell proliferative responses after antigen receptor engagement due to failure of NF-kappaB activation. [provided by MGI curators]
|Amino Acid Change|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000048376] [ENSMUSP00000153585]|
|Predicted Effect||probably benign|
|Predicted Effect||probably benign|
|Phenotypic Category||Autosomal Recessive|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2016-05-13 3:09 PM by Anne Murray|
|Record Created||2015-09-15 2:27 PM|
The bryce_canyon phenotype was identified by gene-based superpedigree analysis among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R0319, some of which showed diminished T-dependent antibody responses to ovalbumin administered with aluminum hydroxide (Figure 1) and recombinant Semliki Forest virus (rSFV)-encoded β-galactosidase (rSFV-β-gal) (Figure 2). The T-independent antibody response to 4-hydroxy-3-nitrophenylacetyl-Ficoll (NP-Ficoll) was also diminished (Figure 3).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire in the R0319 pedigree identified 56 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Malt1 by gene-based superpedigree analysis: a T to C transition at base pair 65,462,915 (v38) on chromosome 18, or base pair 31,947 in the NC_000084 GenBank genomic region within the donor splice site of intron 10 (2 base pairs from exon 10). The strongest association was found with a recessive model of linkage to the T-dependent antibody response to rSFV-β-gal, wherein five variant homozygotes from three pedigrees departed phenotypically from 29 homozygous reference mice and 45 heterozygous mice with a P value of 4.604 x 10-9 (Figure 4). A substantial semidominant effect was observed in most of the assays but the mutation is preponderantly recessive, and in no assay was a purely dominant effect observed.
The effect of the mutation at the cDNA and protein level have not examined, but the mutation is predicted to result in skipping of the 178-base pair exon 10 (out of 16 total exons), resulting in a frame-shift and coding of 13 aberrant amino acids followed by a premature stop codon within exon 11 (after amino acid 418).
Genomic numbering corresponds to NC_000084. The donor splice site of intron 11, which is destroyed by the bryce_canyon mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
Malt1 encodes mucosa-associated lymphoid tissue translocation gene 1 (MALT1; alternatively paracaspase; Figure 5). MALT1 has several domains including a death domain (DD; amino acids 45-132), a paracaspase domain (amino acids 340-535), and three immunoglobulin (Ig)-like domains [amino acids 145-203 (Ig1), 248-306 (Ig2), and 581-715 (Ig3)] (1). The mutation in bryce_canyon is predicted to result in deletion of amino acids 406-464 as well as a frameshift after amino acid 405, coding of 13 aberrant amino acids followed by a premature stop codon.
For more information about Malt1, please see the record mousebird.
Upon T cell activation by the TCR and costimulatory molecule engagement, CARMA1 associates with a complex containing Bcl10 and MALT1 and recruits these proteins to lipid rafts of the immunological synapse and to form a scaffold for the assembly of several signaling complexes including those that involve TNF receptor-associated factor 6 (TRAF6), TGF (transforming growth factor)-β-activated kinase 1 (TAK1), and NF-κB essential modulator (NEMO; see the record for panr2) to facilitate NF-κB activation and lymphocyte stimulation. In addition to T and B cells, MALT1 functions in mast cells, dendritic cells, macrophages and natural killer (NK) cells (2-4). Malt1-/- mice exhibit defective antigen receptor-induced lymphocyte activation (5;6). Malt1-/- mice exhibited reduced T-dependent antibody responses to keyhole limpet haemocyanin (KLH) in complete Freund's adjuvant (CFA) and 2,4-dinitrophenol–conjugated ovalbumin (DNP-OVA) as well as reduced T-independent antibody responses to tri-nitrophenol-(TNP)-Ficoll (5-7). The bryce_canyon mice also exhibit defects in both T-independent and T-dependent antibody responses indicating that the MALT1bryce_canyon protein, if expressed, exhibits loss-of-function.
bryce_canyon(F):5'- AGGATTGTTATATTATGCAGGGCACGG -3'
bryce_canyon(R):5'- ACTGCTAGTCACATGGACATGGACTC -3'
bryce_canyon_seq(F):5'- GGCACGGTTATGAAAACTTTGG -3'
bryce_canyon_seq(R):5'- TATAACTTGTACCTTTCACAGCAAAC -3'
1. Uren, A. G., O'Rourke, K., Aravind, L. A., Pisabarro, M. T., Seshagiri, S., Koonin, E. V., and Dixit, V. M. (2000) Identification of Paracaspases and Metacaspases: Two Ancient Families of Caspase-Like Proteins, One of which Plays a Key Role in MALT Lymphoma. Mol Cell. 6, 961-967.
2. Thome, M. (2004) CARMA1, BCL-10 and MALT1 in Lymphocyte Development and Activation. Nat Rev Immunol. 4, 348-359.
3. Klemm, S., Gutermuth, J., Hultner, L., Sparwasser, T., Behrendt, H., Peschel, C., Mak, T. W., Jakob, T., and Ruland, J. (2006) The Bcl10-Malt1 Complex Segregates Fc Epsilon RI-Mediated Nuclear Factor Kappa B Activation and Cytokine Production from Mast Cell Degranulation. J Exp Med. 203, 337-347.
4. Gross, O., Grupp, C., Steinberg, C., Zimmermann, S., Strasser, D., Hannesschlager, N., Reindl, W., Jonsson, H., Huo, H., Littman, D. R., Peschel, C., Yokoyama, W. M., Krug, A., and Ruland, J. (2008) Multiple ITAM-Coupled NK-Cell Receptors Engage the Bcl10/Malt1 Complex Via Carma1 for NF-kappaB and MAPK Activation to Selectively Control Cytokine Production. Blood. 112, 2421-2428.
5. Ruefli-Brasse, A. A., French, D. M., and Dixit, V. M. (2003) Regulation of NF-kappaB-Dependent Lymphocyte Activation and Development by Paracaspase. Science. 302, 1581-1584.
6. Ruland, J., Duncan, G. S., Wakeham, A., and Mak, T. W. (2003) Differential Requirement for Malt1 in T and B Cell Antigen Receptor Signaling. Immunity. 19, 749-758.
|Science Writers||Anne Murray|
|Authors||Jin Huk Choi, Kuan-Wen Wang, and Bruce Beutler|
|List [record 53 of 0]|