Strain Detail Sheet

Genetic Alterations:
The Ikbkg gene on the X chromosome of panr2 mice was sequenced, and a T to C transition was identified in exon 4 (of 10 total exons) at position 473 (using variant 1, Genbank: NM_178590). The mutation results in a leucine to proline change at amino acid 153 of the IKK-Υ or NEMO protein.

Genotype Determination:

• PCR Genotyping Protocol

ES Cell Line: Not Applicable

Phenotype
Homozygous and Hemizygous phenotype: The panr2 ("pan- resistance") phenotype was detected in a screen of ENU-induced mutant mice for altered responses to Toll-like receptor (TLR) ligands (TLR Signaling Screen). Peritoneal macrophages from panr2 mice exhibit low tumor necrosis factor (TNF)-α production to all TLR ligands except the TLR4 ligand, lipopolysaccharide (LPS). Only a subtle reduction in TNF-α production is seen in these macrophages when stimulated with LPS. In response to the TLR3 ligand poly I:C (a dsRNA mimetic) and dsDNA, panr2 macrophages display normal type 1 interferon (IFN) production. Panr2 mice display normal natural killer (NK) cell and cytotoxic T cell (CTL) function (In vivo NK cell and CD8+ T cell cytotoxicity screen).

Although the TLR sensing defect remains as reported and hemizygous males remain azoospermatic, this mutation is no longer associated with male lethality.

Mammalian Phenotype Terms:(provided by MGI)      Extend all MPTs
      assigned by genotype

Ikbkg^m1Btlr/Ikbkg⁺

        C57BL/6J-Ikbkg<m1Btlr>

• reproductive system phenotype
  • reduced female fertility (MGI Ref ID J:139558)
    • female mice heterozygous for this mutation are poor breeders

Ikbkg^m1Btlr/-

        C57BL/6J-Ikbkg<m1Btlr>

• mortality/aging
  • mortality/aging (MGI Ref ID J:139558)
    • despite earlier reports that hemizygous males are born at a lower-than-expected frequency, larger numbers of births showed that hemizygotes are born at the expected Mendelian ratio; they survive for at least 4-6 weeks
• reproductive system phenotype
  • azoospermia (MGI Ref ID J:139558)
• immune system phenotype
  • immune system phenotype (MGI Ref ID J:139558)
    • type 1 interferon (IFN) production by macrophages from hemizygous mutant male mice in response to the toll-like receptor (TLR) 3 ligand poly I:C (a dsRNA mimetic) and to dsDNA is normal
    • mutant mice have normal CD8⁺ lymphocyte function
    • decreased regulatory T cell number (MGI Ref ID J:139558)
      • mutant mice have a two-fold reduction in peripheral CD4⁺CD25⁺ lymphocytes (regulatory T cells)
    • decreased tumor necrosis factor secretion (MGI Ref ID J:139558)
      • upon stimulation with the TLR4 ligand, lipopolysaccharide (LPS), peritoneal macrophages from hemizygous mutant male mice exhibit a s ubtly reduced TNF-alpha response compared to that of wild-type mice
      • mutant macrophages produce normal amounts of tumor necrosis factor (TNF) alpha in response to stimulation with all other toll-like receptor (TLR) ligands tested: the TLR3 ligand poly(I:C); the TLR1/2 ligand Pam3CSK4; the TLR7 ligand resiquimod; the TLR9 ligand CpG ODN; and the TLR6 ligands peptidoglycan and MALP-2
• hematopoietic system phenotype
  • decreased regulatory T cell number (MGI Ref ID J:139558)
    • mutant mice have a two-fold reduction in peripheral CD4⁺CD25⁺ lymphocytes (regulatory T cells)

Founder genetic background: C57BL/6

Strain genetic background: C57BL/6J

Strain Development: Original mutant was a C57BL/6J G3 ENU-induced mutant; all subsequent crosses to maintain strain were on C57BL/6J background only.

Suggested Control Mice: Wild-type littermates or C57BL/6J

• Immunology and Inflammation
• Models for Human Disease

Donor: Bruce Beutler, M.D., The Scripps Research Institute

Primary Reference:

• Siggs OM, Berger M, Krebs P, Arnold CN, Eidenschenk C, Huber C, Pirie E, Smart NG, Khovananth K, Xia Y, McInerney G, Karlsson Hedestam GB, Nemazee D, Beutler B. A mutation of Ikbkg causes immune deficiency without impairing degradation of IkappaB alpha. Proc Natl Acad Sci U S A 2010 Feb 16;107(7):3046-51 (Medline PMID: 20133626)
• Siggs OM, Smart NG, Beutler B. Record for panr2. MUTAGENETIX™, B. Beutler and colleagues, The Scripps Research Institute, La Jolla, CA.

Coat color: Black

Other:

MMRRC Breeding System: Random intra-strain mating

Breeding Scheme(s):

• Heterozygous female x C57BL/6J male.

Generation:

Overall Breeding Performance: Fair

NOTE: "Hemizygote" as used here refers to males carrying a mutation on the X Chromosome or mice of either sex carrying an inserted transgene with no homologous allele on the other chromosome.

Average litter size:

Recommended wean age: 3 weeks

Mice recovered from a cryo-archive will have health surveillance performed on recipient females. Health reports will be provided prior to shipment. If you require additional health status information, please email mmrrc@ucdavis.edu.