Mouse Genome Informatics
hm1
    Atmtm1Awb/Atmtm1Awb
either: 129S6/SvEvTac-Atmtm1Awb or (involves: 129S6/SvEvTac * NIH Black Swiss)
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Oxidated stress in the brain of Atmtm1Awb/Atmtm1Awb mice indicated by increased levels of heme oxygenase

mortality/aging
• mutant mice die from radiation induced toxicity to the gastrointestinal tract at doses that do not kill control mice
• many mice die from thymic lymphoma; none survived greater than 4.5 months of age without a thymic lymphoma

growth/size
• homozygotes appear smaller at birth
• female and male homozygotes weigh less that control littermates from P8 to 3 months of age

immune system
N
• no abnormalities in B lymphocytes, granulocytes or myeloid cells observed (J:34193)
• reduced number of mature single-positive Cd4+ and Cd8+ T lymphocytes
• using Cd69 as a marker of activation, the number of Cd3/Cd69 or Cd8/Cd69 positive cells is reduced, but still present
• 59% reduction in Cd3/Cd4 double positive T lymphocytes
• 67% reduction in Cd3/Cd8 double positive T lymphocytes
• reduction in Cd5, Cd4, and Cd8 positive T lymphocytes
• increased number of immature double positive cells

reproductive system
• absence of primordial and mature ovarian follicles (J:34193)
(J:34193)
• no proliferation or degeneration in as part of the estrous cycle (J:34193)
• complete absence of mature gametes (J:34193)
• absence of mature sperm (J:34193)
• reduced number of cells (J:34193)
• degeneration of cells evident (J:34193)
• some barren of all cells except Sertoli cells (J:34193)
(J:34193)
• females never enter estrous (J:34193)
• females never exhibit copulation plugs (J:34193)
• normal mating behavior evident by the presence of copulation plugs in control females; however, pregnancy never results (J:34193)

tumorigenesis
• thymic lymphomas are highly metastatic and consist of immature T cells

cellular
• significant increase in the number of lysosomes in cerebellar Purkinje cells and in pyramidal cells of the hippocampus in the absence of any neuronal degeneration at 4-12 weeks of age, before the onset of T cell lymphoma
• mutant fibroblasts show increased radioresistant DNA synthesis (RDS) after 5 to 15 Gy of gamma-irradiation compared to controls, indicating that cell cycle checkpoints are abnormal
• mutant fibroblasts grew more slowly in culture than control cells
• tissues from mutants are under oxidative stress and suffer oxidative damage, especially in the brain
• oxidative damage to proteins and lipids as indicated by elevated nitrotyrosine levels in the brain (but not the liver) and elevated F2-isoprostanes in the testes (indicative of lipid damage)
• activity of the isozyme, heme oxygenase, is increased 600% in the cerebellum (but not in the cortex)

behavior/neurological
• mutant mice were not able to stay on a rota-rod as long as controls
• impaired performance was not due to decreased strength since mice were able to suspend from a wire lid as long as controls
• mutant mice reared less often than controls
• reduced horizontal activity was shown by reduced movement around an open field
• in addition, the maximum difference in stride lengths was greater in mutant mice, suggestive of ataxia

nervous system
N
• no defects in brain architecture (J:34193)
• no evidence of neurodegeneration (J:34193)
• heme oxygenase 1 is increase in Purkinje cells, indicating oxidative damage particularly in these cells

hematopoietic system
• reduced number of mature single-positive Cd4+ and Cd8+ T lymphocytes
• using Cd69 as a marker of activation, the number of Cd3/Cd69 or Cd8/Cd69 positive cells is reduced, but still present
• 59% reduction in Cd3/Cd4 double positive T lymphocytes
• 67% reduction in Cd3/Cd8 double positive T lymphocytes
• reduction in Cd5, Cd4, and Cd8 positive T lymphocytes
• increased number of immature double positive cells

endocrine/exocrine glands
• absence of primordial and mature ovarian follicles (J:34193)
(J:34193)
• reduced number of cells (J:34193)
• degeneration of cells evident (J:34193)
• some barren of all cells except Sertoli cells (J:34193)
(J:34193)

Mouse Models of Human Disease
OMIM IDRef(s)
Ataxia-Telangiectasia; AT 208900 J:34193 , J:57115


Mouse Genome Informatics
hm2
    Atmtm1Awb/Atmtm1Awb
involves: 129S6/SvEvTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• median survival is 16 weeks

immune system
N
• thymic apoptosis following exposure to radiation is normal (J:126920)
• in thymus and spleen
• in thymus and spleen
• B cells have about a 5-fold reduction in class switch recombination to IgG1
• there is small increase in switch junctions showing three or more nucleotide insertions

cellular
N
• mouse embryonic fibroblast cells arrest and undergo apoptosis following exposure to ionizing radiation (J:126186)
• lymphoma cells show Chromosome 14 translocations at the TCR alpha/delta locus
• DNA losses in distal Chromosome 12 near the Igh locus
• mouse embryonic fibroblasts exposed to radiation fail to arrest at the G1/S transition unlike similarly treated wild-type cells
• 10%-20% of B cells harbored IgH-specific breaks, 0.5%-3.5% carried IgH translocations, and 20%-30% had non-IgH associated instability
• incubation with DNA-PKcs kinase inhibitors dramatically increases genomic instability and almost doubles the frequency of myc/IgH translocations

growth/size

hematopoietic system
• in thymus and spleen
• in thymus and spleen
• B cells have about a 5-fold reduction in class switch recombination to IgG1
• there is small increase in switch junctions showing three or more nucleotide insertions

tumorigenesis


Mouse Genome Informatics
hm3
    Atmtm1Awb/Atmtm1Awb
involves: 129S6/SvEvTac * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• majority die with thymic lymphomas by 5 months of age, 2.9% live up to 10 months, and none live beyond 15 months

tumorigenesis
• majority die with thymic lymphomas

cellular
• MEFs exhibit defects in G1/S, intra-S-phase, and G2/M checkpoints after ionizing radiation induced DNA damage


Mouse Genome Informatics
cx4
    Atmtm1Awb/Atmtm1Awb
Pim1tm1Mjn/Pim1+

involves: 129 * 129S6/SvEvTac * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cellular
N
• no defect in homology directed repair is detected in MEFs or ear fibroblasts (J:194229)


Mouse Genome Informatics
cx5
    Atmtm1Awb/Atmtm1Awb
Ppm1dtm1Lad/Ppm1dtm1Lad
Tg(IghMyc)22Bri/0

involves: 129 * C57BL * FVB/N * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• the median lifespan of 69 days

tumorigenesis
• based on median survival time, mice carrying double Atmtm1Awb allele were no more resistant to tumor formation induced by myc than mice with homozygous wild-type Ppm1d+ allele


Mouse Genome Informatics
cx6
    Atmtm1Awb/Atmtm1Awb
Rad52tm1Aps/Rad52tm1Aps

involves: 129P2/OlaHsd * 129S6/SvEvTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• median survival is 33 weeks compared to 16 weeks for Atmtm1Awb homozygotes

tumorigenesis
• unlike in Atmtm1Awb homozygotes, mice rarely develop T cell lymphomas
• mice develop thymic tumors

immune system

growth/size

hematopoietic system


Mouse Genome Informatics
cx7
    Atmtm1Awb/Atmtm1Awb
Nbntm2.1Jpt/Nbntm2.1Jpt

involves: 129S6/SvEvTac * 129/Sv
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cellular
• cells undergo fail to exhibit increased levels of apoptosis following exposure to ionizing radiation


Mouse Genome Informatics
cx8
    Atmtm1Awb/Atmtm1Awb
Nbntm1Jpt/Nbntm1Jpt

involves: 129S6/SvEvTac * 129S7/SvEvBrd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• no embryos detected at E10, stage of death not determined


Mouse Genome Informatics
cx9
    Atmtm1Awb/Atmtm1Awb
Rad50tm2Jpt/Rad50tm2Jpt

involves: 129S6/SvEvTac * 129S7/SvEvBrd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• although die of malignancy, they have a significantly greater survival time than homozygous Rad50tm2Jpt mice, with 42% living longer than 5 months, 20.5% surviving to 10 months and 18% surviving to 15 months

tumorigenesis
• although mutants develop lymphomas, the latency of lymphomagenesis is increased compared to homozygous Atmtm1Awb mice

cellular
N
• growth of MEFs and sensitivity to irradiation is comparable to wild-type indicating rescue of the slower growth of MEFs and increased sensitivity to gamma-irradiation that is seen in homozygous Atmtm1Awb mice (J:103922)
• MEFs exhibit defects in G1/S, intra-S-phase, and G2/M checkpoints after ionizing radiation induced DNA damage
• exhibit some chromosomal instability, however it is slightly reduced relative to homozygous Atm mice

hematopoietic system
• 4 of 42 develop anemia


Mouse Genome Informatics
cx10
    Atmtm1Awb/Atm+
Rad50tm2Jpt/Rad50tm2Jpt

involves: 129S6/SvEvTac * 129S7/SvEvBrd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• although most succumb to anemia, they have a significantly greater survival time than homozygous Rad50tm2Jpt mice, with 85% living longer than 5 months of age

tumorigenesis
• 16 of 67 develop lymphoma

hematopoietic system
• most succumb to anemia
• macrophage counts are decreased to a similar level as in homozygous Atmtm1Awb mice

immune system
• macrophage counts are decreased to a similar level as in homozygous Atmtm1Awb mice