Incidental Mutation 'H8930:Malt1'

• ID: 536
• Institutional Source: Beutler Lab
• Gene Symbol: Malt1
• Ensembl Gene: ENSMUSG00000032688
• Gene Name: MALT1 paracaspase
• Synonyms: D430033E09Rik, paracaspase, Pcasp1
• Essential gene?: Possibly non essential (E-score: 0.428)
• Stock #: H8930 (G3) of strain frazz
• Status: Validated
• Chromosome: 18
• Chromosomal Location: 65564010-65611959 bp(+) (GRCm39)
• Type of Mutation: nonsense
• DNA Base Change (assembly): T to G at 65595886 bp (GRCm39)
• Zygosity: Heterozygous
• Amino Acid Change: Tyrosine to Stop codon at position 442 (Y442*)
• Ref Sequence: ENSEMBL: ENSMUSP00000153585
• Gene Model: predicted gene model for transcript(s): [ENSMUST00000049248] [ENSMUST00000224056]
• AlphaFold: Q2TBA3
• Predicted Effect: probably null; Transcript: ENSMUST00000049248; AA Change: Y431*
• SMART Domains: Protein: ENSMUSP00000048376; Gene: ENSMUSG00000032688; AA Change: Y431*

Domain	Start	End	E-Value	Type
low complexity region	19	35	N/A	INTRINSIC
low complexity region	38	51	N/A	INTRINSIC
PDB:2G7R|B	52	132	3e-29	PDB
IGc2	145	203	8.19e-9	SMART
IGc2	248	306	2.88e-4	SMART
Pfam:Peptidase_C14	340	557	1.4e-19	PFAM

• Predicted Effect: probably null; Transcript: ENSMUST00000224056; AA Change: Y442*
• Predicted Effect: noncoding transcript; Transcript: ENSMUST00000224265
• Meta Mutation Damage Score: 0.9755
• Coding Region Coverage:
  • 1x: 77.1%
  • 3x: 50.6%
• Het Detection Efficiency: 25.5%
• Validation Efficiency: 74% (89/120)
• MGI Phenotype: 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]
• Allele List at MGI:

  All alleles(7) : Targeted, knock-out(2) Targeted, other(2) Gene trapped(3)

• Posted On: 2010-11-11

Nature of Mutation

DNA sequencing using the SOLiD technique identified a T to G transition at position 1468 of the Malt1transcript in exon 10 of 16 total exons. Two transcripts of the Malt1 gene are displayed on Ensembl. The mutated nucleotide introduces a premature stop codon at tyrosine 431 of the encoded protein. The mutation has been confirmed by DNA sequencing using the Sanger method (Figure 1).

Protein Function and Prediction

The Malt1 gene encodes an 832 amino acid protein that belongs to the peptidase C14B family and is known as paracaspase. Paracaspase has ubiquitin ligase activity and acts together with Bcl10 and caspase recruitment domain family, member 11 (CARMA1) to activate the I-kappaB complex and induce NF-kappaB activation downstream of the B and T cell receptors. Paracaspase binds to and activates the ubiquitin ligase TRAF6. Multiple isoforms are produced by alternative splicing. Paracaspase contains a Death domain at residues 45-132, two immunoglobulin (Ig)-like C2-type domains at residues 131-207 and 218-314, and a caspase-like region at residues 356-570. A nuclear export signal is located at amino acids 377-384 (Uniprot Q2TBA3). Primary T- and B-cell lymphocytes from homozgyous knockout mice are defective in antigen receptor-induced NF-kappa-B activation, cytokine production, and proliferation.

The premature stop introduced by the Frazz mutation in the Malt1 gene truncates 402 amino acids from the C-terminus of the protein. This allele is likely null.