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 Euro Europhenome
N normal phenotype

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

mortality/aging
increased mortality induced by gamma-irradiation ( J:34193 )
• mutant mice die from radiation induced toxicity to the gastrointestinal tract at doses that do not kill control mice
premature death ( J:34193 )
• many mice die from thymic lymphoma; none survived greater than 4.5 months of age without a thymic lymphoma

growth/size
decreased body size ( J:34193 )
• homozygotes appear smaller at birth
decreased body weight ( J:34193 )
• female and male homozygotes weigh less that control littermates from P8 to 3 months of age

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

reproductive system
absent ovarian follicles ( J:34193 )
• absence of primordial and mature ovarian follicles (J:34193)
small ovary ( J:34193 )
(J:34193)
abnormal uterus morphology ( J:34193 )
• no proliferation or degeneration in as part of the estrous cycle (J:34193)
absent oocytes ( J:34193 )
• complete absence of mature gametes (J:34193)
azoospermia ( J:34193 )
• absence of mature sperm (J:34193)
abnormal seminiferous tubule morphology ( J:34193 )
• reduced number of cells (J:34193)
• degeneration of cells evident (J:34193)
• some barren of all cells except Sertoli cells (J:34193)
small testis ( J:34193 )
(J:34193)
absent estrus ( J:34193 )
• females never enter estrous (J:34193)
female infertility ( J:34193 )
• females never exhibit copulation plugs (J:34193)
male infertility ( J:34193 )
• normal mating behavior evident by the presence of copulation plugs in control females; however, pregnancy never results (J:34193)

tumorigenesis
T cell derived lymphoma ( J:34193 )
• thymic lymphomas are highly metastatic and consist of immature T cells

cellular
abnormal lysosome morphology ( J:59933 )
• 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
increased cellular sensitivity to gamma-irradiation ( J:34193 )
• 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
decreased double-positive T cell number ( J:34193 )
• 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 double-positive T cell number ( J:34193 )
• increased number of immature double positive cells
decreased fibroblast proliferation ( J:34193 )
• mutant fibroblasts grew more slowly in culture than control cells
oxidative stress ( J:57115 )
• 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
impaired coordination ( J:34193 )
• 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
decreased vertical activity ( J:34193 )
• mutant mice reared less often than controls
hypoactivity ( J:34193 )
• reduced horizontal activity was shown by reduced movement around an open field
short stride length ( J:34193 )
• in addition, the maximum difference in stride lengths was greater in mutant mice, suggestive of ataxia

nervous system
nervous system phenotype ( J:34193 )
N
• no defects in brain architecture (J:34193)
• no evidence of neurodegeneration (J:34193)
abnormal Purkinje cell morphology ( J:57115 )
• heme oxygenase 1 is increase in Purkinje cells, indicating oxidative damage particularly in these cells

hematopoietic system
increased double-positive T cell number ( J:34193 )
• increased number of immature double positive cells
decreased T cell number ( J:34193 )
• reduced number of mature single-positive Cd4+ and Cd8+ T lymphocytes
decreased double-positive T cell number ( J:34193 )
• 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
decreased activated T cell number ( J:34193 )
• using Cd69 as a marker of activation, the number of Cd3/Cd69 or Cd8/Cd69 positive cells is reduced, but still present

endocrine/exocrine glands
absent ovarian follicles ( J:34193 )
• absence of primordial and mature ovarian follicles (J:34193)
small ovary ( J:34193 )
(J:34193)
abnormal seminiferous tubule morphology ( J:34193 )
• reduced number of cells (J:34193)
• degeneration of cells evident (J:34193)
• some barren of all cells except Sertoli cells (J:34193)
small testis ( 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 Euro Europhenome
N normal phenotype
mortality/aging
premature death ( J:90941 )
• median survival is 16 weeks

immune system
immune system phenotype ( J:126920 )
N
• thymic apoptosis following exposure to radiation is normal (J:126920)
abnormal class switch recombination ( J:150435 )
• 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
decreased CD4-positive T cell number ( J:90941 )
• in thymus and spleen
decreased CD8-positive T cell number ( J:90941 )
• in thymus and spleen

cellular
cellular phenotype ( J:126186 )
N
• mouse embryonic fibroblast cells arrest and undergo apoptosis following exposure to ionizing radiation (J:126186)
abnormal chromosome morphology ( J:170462 )
• lymphoma cells show Chromosome 14 translocations at the TCR alpha/delta locus
• DNA losses in distal Chromosome 12 near the Igh locus
abnormal cell cycle checkpoint function ( J:126920 )
• mouse embryonic fibroblasts exposed to radiation fail to arrest at the G1/S transition unlike similarly treated wild-type cells
abnormal class switch recombination ( J:150435 )
• 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
spontaneous chromosome breakage ( J:150435 )
• 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
abnormal class switch recombination ( J:150435 )
• 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
decreased CD4-positive T cell number ( J:90941 )
• in thymus and spleen
decreased CD8-positive T cell number ( J:90941 )
• in thymus and spleen

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 Euro Europhenome
N normal phenotype
mortality/aging
premature death ( J:103922 )
• majority die with thymic lymphomas by 5 months of age, 2.9% live up to 10 months, and none live beyond 15 months

tumorigenesis
T cell derived lymphoma ( J:103922 )
• majority die with thymic lymphomas

cellular
abnormal cell cycle checkpoint function ( J:103922 )
• 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
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 Euro Europhenome
N normal phenotype
mortality/aging
premature death ( J:120284 )
• the median lifespan of 69 days

tumorigenesis
increased tumor incidence ( J:120284 )
• 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
cx5
     Atmtm1Awb/Atmtm1Awb
Rad52tm1Aps/Rad52tm1Aps
involves: 129P2/OlaHsd * 129S6/SvEvTac
Key:
♀ phenotype observed in females WTSI Wellcome Trust Sanger Institute
♂ phenotype observed in males Euro Europhenome
N normal phenotype
mortality/aging
premature death ( J:90941 )
• median survival is 33 weeks compared to 16 weeks for Atmtm1Awb homozygotes

tumorigenesis
decreased lymphoma incidence ( J:90941 )
• unlike in Atmtm1Awb homozygotes, mice rarely develop T cell lymphomas
T cell derived lymphoma ( J:90941 )
• mice develop thymic tumors

immune system

growth/size

hematopoietic system


Mouse Genome Informatics
cx6
     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 Euro Europhenome
N normal phenotype
cellular
decreased cellular sensitivity to ionizing radiation ( J:129762 )
• cells undergo fail to exhibit increased levels of apoptosis following exposure to ionizing radiation


Mouse Genome Informatics
cx7
     Atmtm1Awb/Atmtm1Awb
Nbntm1Jpt/Nbntm1Jpt
involves: 129S6/SvEvTac * 129S7/SvEvBrd
Key:
♀ phenotype observed in females WTSI Wellcome Trust Sanger Institute
♂ phenotype observed in males Euro Europhenome
N normal phenotype
mortality/aging
complete embryonic lethality ( J:75956 )
• no embryos detected at E10, stage of death not determined


Mouse Genome Informatics
cx8
     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 Euro Europhenome
N normal phenotype
mortality/aging
premature death ( J:103922 )
• 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
increased lymphoma incidence ( J:103922 )
• although mutants develop lymphomas, the latency of lymphomagenesis is increased compared to homozygous Atmtm1Awb mice

cellular
cellular phenotype ( J:103922 )
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)
abnormal cell cycle checkpoint function ( J:103922 )
• MEFs exhibit defects in G1/S, intra-S-phase, and G2/M checkpoints after ionizing radiation induced DNA damage
chromosome breakage ( J:103922 )
• exhibit some chromosomal instability, however it is slightly reduced relative to homozygous Atm mice

hematopoietic system
anemia ( J:103922 )
• 4 of 42 develop anemia


Mouse Genome Informatics
cx9
     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 Euro Europhenome
N normal phenotype
mortality/aging
premature death ( J:103922 )
• 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
increased lymphoma incidence ( J:103922 )
• 16 of 67 develop lymphoma

hematopoietic system
anemia ( J:103922 )
• most succumb to anemia
decreased macrophage cell number ( J:103922 )
• macrophage counts are decreased to a similar level as in homozygous Atmtm1Awb mice

immune system
decreased macrophage cell number ( J:103922 )
• macrophage counts are decreased to a similar level as in homozygous Atmtm1Awb mice