Mouse Genome Informatics
hm1
    Atmtm1Fwa/Atmtm1Fwa
involves: 129S4/SvJae
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• mice are born in Mendelian ratios (J:191288)

cellular
• embryonic stem cells exhibit increased spontaneous cytogenetic abnormalities (predominantly chromosome breaks) compared with wild-type cells
• B cells from tamoxifen-treated mice exhibit reduced class switch recombination with increased genomic instability compared with wild-type cells

immune system
• B cells from tamoxifen-treated mice exhibit reduced class switch recombination with increased genomic instability compared with wild-type cells

hematopoietic system
• B cells from tamoxifen-treated mice exhibit reduced class switch recombination with increased genomic instability compared with wild-type cells


Mouse Genome Informatics
hm2
    Atmtm1Fwa/Atmtm1Fwa
involves: 129S4/SvJae * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Dendritic changes in Purkinje cells of Atmtm1Fwa/Atmtm1Fwa mice

mortality/aging
• death in mice carrying thymic lymphomas occcurs by 4-5 months of age
• 50% of mice survive 10 months or more

growth/size
• approximately a 20% reduction in body weight is observed

tumorigenesis
• T cell-derived lymphomas frequently resulted in premature death

immune system
• only 40-50% of the normal levels of thymocytes and splenocytes are seen
• reduced numbers of immature B cells in bone marrow
• reduced numbers of precursor B cells in bone marrow
• mature B cell numbers are similar to controls
• 8-10 fold reduction in splenic T cell numbers
• 2-fold decrease in double positive and a 5-fold decrease in single positive thymocytes
• only 40-50% of the normal levels of splenocytes are seen

behavior/neurological
• mice do not exhibit improvement over time on the accelerating rotarod test
• adult mice tend to explore an open field less than controls

nervous system
• Purkinje cell axons exhibit varicosities in the internal granule cell layer; however, these swellings are small and unlike the large axonal swellings seen in human Ataxia-Telangiectasia patients
• irregular pattern of dendrites; consistently branch prematurely and have multiple dendrites originating from one cell body
• dendrites often project at odd angles in the molecular layer
• Purkinje cell bodies are seen in the molecular layer
• the cerebellum molecular layer is approximately 13% thinner than controls

reproductive system
(J:61201)

cellular
• homozygous cells were hypersensitive to irradiation (data not shown)

hematopoietic system
• only 40-50% of the normal levels of thymocytes and splenocytes are seen
• reduced numbers of immature B cells in bone marrow
• reduced numbers of precursor B cells in bone marrow
• mature B cell numbers are similar to controls
• 8-10 fold reduction in splenic T cell numbers
• 2-fold decrease in double positive and a 5-fold decrease in single positive thymocytes
• only 40-50% of the normal levels of splenocytes are seen

Mouse Models of Human Disease
OMIM IDRef(s)
Ataxia-Telangiectasia; AT 208900 J:61201


Mouse Genome Informatics
cx3
    Atmtm1Fwa/Atmtm1Fwa
H2afxtm1Fwa/H2afxtm1Fwa

involves: 129S4/SvJae * 129S6/SvEvTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• because the two genes are 4 cm apart, the cross of heterozygote parents resulted in a 4% cross-over frequency of which half (2%) of the cross-overs had the two null alleles linked
• breeding of these progeny resulted in embryonic lethality in the double homozygotes
• half the embryos are dead at E11.5 and all embryos dead by E12.5
• embryos had pleiotropic developmental defects associated with increased cell death and decreased mitotic index

cellular
• freshly isolated E10.5 MEFs have a dramatic increase in the sub-G1 population, indicative of massive cell death
• 80% of E10.5 MEFs have cytogenetic abnormalities compared to 2-3% in wild-type controls
• MEF metaphases contained numerous breaks per metaphase (average more than three abnormalities per abnormal metaphase), in contrast to one or, rarely, two aberrations per abnormal metaphase for controls


Mouse Genome Informatics
cx4
    Atmtm1Fwa/Atmtm1Fwa
Pknox1tm1Fbla/Pknox1+

involves: 129S4/SvJae * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
embryogenesis
• in 2 of 4 mice

growth/size
• in 2 of 4 mice


Mouse Genome Informatics
cx5
    Atmtm1Fwa/Atmtm1Fwa
Pknox1tm1Fbla/Pknox1tm1Fbla

involves: 129S4/SvJae * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging

embryogenesis
• at E7.5, Oct4+ cells are almost undetectable in the single mouse generated
• in the single mouse generated

growth/size
• in the single mouse generated