Mouse Genome Informatics
cn1
    Tg(Cr2-cre)3Cgn/?
Xrcc4tm1Fwa/Xrcc4tm2Fwa

involves: 129P2/OlaHsd * 129S6/SvEvTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cellular
• genomic stability is disrupted in activated B cells with chromosome breakage occurring in close to half of cells
• B cells undergoing class switch recombination have even greater increased risk of chromosome breakage due to aberrations at the Igh locus
• there is also increased breakage at the Igk and Igl loci with 1% of stimulated B cells demonstrating this
• Igl breaks in activated B cells are frequently fused to AID-dependent Igh breaks in the same cell to form chromosome 12/16 translocations
• there is also a five-fold increase in Igh-Myc translocations activated B cells compared to controls

hematopoietic system
• class switch recombination often leads to chromosome breakage at the Igh locus

immune system
• class switch recombination often leads to chromosome breakage at the Igh locus


Mouse Genome Informatics
cn2
    Aicdatm1Hon/Aicdatm1Hon
Tg(Cr2-cre)3Cgn/?
Xrcc4tm1Fwa/Xrcc4tm2Fwa

involves: 129P2/OlaHsd * 129S6/SvEvTac * C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cellular
• genomic stability is disrupted in activated B cells with chromosome breakage occurring in close to half of cells
• however, there is no increased breakage of the Igh locus compared to wild-type controls
• there is increased breakage at the Igk and Igl loci with 1% of stimulated B cells demonstrating this


Mouse Genome Informatics
cn3
    Lig4tm1Fwa/Lig4tm1Fwa
Tg(Cr2-cre)3Cgn/0
Xrcc4tm2Fwa/Xrcc4tm2Fwa

involves: 129S6/SvEvTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• class switching to IgG1 is 20% to 50% of wild-type
• class switching to IgG3 is 50% of wild-type
• IgH class switching is reduced compared to in wild-type B cells

cellular
• B cell stimulated with anti-CD40 and IL4 exhibit metaphase chromosome breaks unlike similarly treated wild-type cells

hematopoietic system
• class switching to IgG1 is 20% to 50% of wild-type
• class switching to IgG3 is 50% of wild-type
• IgH class switching is reduced compared to in wild-type B cells


Mouse Genome Informatics
cn4
    Trp53tm1Brd/Trp53+
Xrcc4tm2.1Fwa/Xrcc4tm2Fwa
Tg(Nes-cre)1Kln/0

involves: 129S6/SvEvTac * 129S7/SvEvBrd * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• mice survive beyond 16 months (J:109585)


Mouse Genome Informatics
cn5
    Trp53tm1Brd/Trp53tm1Brd
Xrcc4tm2.1Fwa/Xrcc4tm2Fwa
Tg(Nes-cre)1Kln/0

involves: 129S6/SvEvTac * 129S7/SvEvBrd * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice become moribund between 12 and 14 weeks of age with 20/23 mice dead by 25 weeks

nervous system
• mice at 4 and 8.5 weeks of age show multifocal tumor masses expanding from the granular layer
• at 12-14 weeks mice have aggressive medulloblastomas in the vermis or hemisphere

craniofacial
• at 12-14 weeks skulls of mice show rapid morphological enlargement

skeleton
• at 12-14 weeks skulls of mice show rapid morphological enlargement

tumorigenesis
• mice develop medulloblastomas

Mouse Models of Human Disease
OMIM IDRef(s)
Medulloblastoma; MDB 155255 J:109585


Mouse Genome Informatics
cx6
    Rag2tm1Cgn/Rag2tm1Cgn
Tg(Cr2-cre)3Cgn/?
Xrcc4tm1Fwa/Xrcc4tm2Fwa

involves: 129P2/OlaHsd * 129S6/SvEvTac * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cellular
• genomic stability is disrupted in activated B cells with chromosome breakage occurring in close to half of cells
• B cells undergoing class switch recombination have even greater increased risk of chromosome breakage due to aberrations at the Igh locus
• there is decreased breakage at Igl locus compared to conditional knockouts on a Rag-sufficient background

hematopoietic system
• class switch recombination often leads to chromosome breakage at the Igh locus

immune system
• class switch recombination often leads to chromosome breakage at the Igh locus