Phenotypes associated with this allele

• Allele Symbol: Nhej1^tm1Fwa
• Allele Name: targeted mutation 1, Frederick W Alt
• Allele ID: MGI:3809930
• Summary: 6 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Nhej1^tm1Fwa/Nhej1^tm1Fwa	129S6/SvEvTac-Nhej1^tm1Fwa	MGI:3809934
hm2	Nhej1^tm1Fwa/Nhej1^tm1Fwa	involves: 129	MGI:3809979
cx3	Nhej1^tm1Fwa/Nhej1^tm1Fwa Trp53^tm1Tyj/Trp53^tm1Tyj	involves: 129	MGI:3809981
cx4	Nhej1^tm1Fwa/Nhej1^tm1Fwa Xrcc5^tm1Nus/Xrcc5^tm1Nus	involves: 129S6/SvEvTac * C57BL/6	MGI:5829791
cx5	Cyren^tm1.1(KOMP)Vlcg/Cyren^tm1.1(KOMP)Vlcg Nhej1^tm1Fwa/Nhej1^tm1Fwa	involves: 129S6/SvEvTac * C57BL/6NTac	MGI:6400579
cx6	Paxx^em1Spj/Paxx^em1Spj Nhej1^tm1Fwa/Nhej1^tm1Fwa	involves: 129S6/SvEvTac * C57BL/6NTac	MGI:5827971

Genotype
MGI:3809934

hm1

• Allelic Composition: Nhej1^tm1Fwa/Nhej1^tm1Fwa
• Genetic Background: 129S6/SvEvTac-Nhej1^tm1Fwa

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

cellular

increased cellular sensitivity to gamma-irradiation induced cell death ( J:120145 )

• ES cells are very sensitive to irradiation as determined by colony survival assay with 10-fold less survival at a dose of 400 rads

abnormal DNA repair ( J:120145 )

• 18 hours after 80 Gy of gamma-irradiation, significant amounts of genomic DNA leak out of these ES cells during pulse-field electrophoresis while wild-type ES cells are able retain their genomic material

spontaneous chromosome breakage ( J:120145 )

• untreated ES cells have a high incidence of chromosomal breaks and translocations

• almost 15% of cells exhibit abnormal metaphases with most of these abnormalities resulting from chromosome breaks

• the incidence of chromosome breakages is significantly higher than in wild-type ES cells but was only half that of Xrcc4^tm1Fwa homozygotes

homeostasis/metabolism

increased cellular sensitivity to gamma-irradiation induced cell death ( J:120145 )

• ES cells are very sensitive to irradiation as determined by colony survival assay with 10-fold less survival at a dose of 400 rads

abnormal DNA repair ( J:120145 )

• 18 hours after 80 Gy of gamma-irradiation, significant amounts of genomic DNA leak out of these ES cells during pulse-field electrophoresis while wild-type ES cells are able retain their genomic material

Genotype
MGI:3809979

hm2

• Allelic Composition: Nhej1^tm1Fwa/Nhej1^tm1Fwa
• Genetic Background: involves: 129

cellular

increased cellular sensitivity to gamma-irradiation induced cell death ( J:138774 )

• MEF cells are very sensitive to irradiation as determined by colony survival assay with almost 10-fold less survival at a dose of 4 Gy

spontaneous chromosome breakage ( J:138774 )

• untreated MEF cells have a high incidence of chromosomal breaks and translocations

• almost 13% of cells exhibit abnormal metaphases with most of these abnormalities resulting from chromosome breaks compared to only 1% of wild-type MEFs

hematopoietic system

thymus hypoplasia ( J:138774 )

• total cell numbers in the thymus of 4 week old mice are about 40-50% of the numbers found in wild-type mice

• proportions of the developing T cell subsets remains normal

abnormal class switch recombination ( J:138774 )

• only 23% of B cells stimulated in vitro in the presence of IL-4 switch to an IgG1 B cell receptor while 46% of wild-type B cells switch to IgG1

• LPS stimulation leads to only 4% of B cells switching to IgG3 while 9% of wild-type B cells switch to IgG3

• FISH analysis of B cells stimulated in the presence of IL-4 demonstrates 9% of B cell metaphases contain chromosomal breaks of the IgH locus compared with 2% for wild-type B cell metaphases

• an increased proportion of B cells have microhomology (MH) joins at the sites of class switch recombination, with the MH joins being on average longer than those found in controls

spleen hypoplasia ( J:138774 )

• total cell numbers in the spleen of 4 week old mice are about 40-50% of the numbers found in wild-type mice

decreased IgG1 level ( J:138774 )

• IgG1 levels are slightly decreased in the sera of 6 week old mice compared to controls

decreased IgG3 level ( J:138774 )

• IgG3 levels are significantly decreased in the sera of 6 week old mice compared to controls

increased IgM level ( J:138774 )

• IgM levels in the sera of 6 week old mice are slightly higher than in wild-type controls

immune system

thymus hypoplasia ( J:138774 )

• total cell numbers in the thymus of 4 week old mice are about 40-50% of the numbers found in wild-type mice

• proportions of the developing T cell subsets remains normal

abnormal class switch recombination ( J:138774 )

• only 23% of B cells stimulated in vitro in the presence of IL-4 switch to an IgG1 B cell receptor while 46% of wild-type B cells switch to IgG1

• LPS stimulation leads to only 4% of B cells switching to IgG3 while 9% of wild-type B cells switch to IgG3

• FISH analysis of B cells stimulated in the presence of IL-4 demonstrates 9% of B cell metaphases contain chromosomal breaks of the IgH locus compared with 2% for wild-type B cell metaphases

• an increased proportion of B cells have microhomology (MH) joins at the sites of class switch recombination, with the MH joins being on average longer than those found in controls

spleen hypoplasia ( J:138774 )

• total cell numbers in the spleen of 4 week old mice are about 40-50% of the numbers found in wild-type mice

decreased IgG1 level ( J:138774 )

• IgG1 levels are slightly decreased in the sera of 6 week old mice compared to controls

decreased IgG3 level ( J:138774 )

• IgG3 levels are significantly decreased in the sera of 6 week old mice compared to controls

increased IgM level ( J:138774 )

• IgM levels in the sera of 6 week old mice are slightly higher than in wild-type controls

endocrine/exocrine glands

thymus hypoplasia ( J:138774 )

• total cell numbers in the thymus of 4 week old mice are about 40-50% of the numbers found in wild-type mice

• proportions of the developing T cell subsets remains normal

homeostasis/metabolism

increased cellular sensitivity to gamma-irradiation induced cell death ( J:138774 )

• MEF cells are very sensitive to irradiation as determined by colony survival assay with almost 10-fold less survival at a dose of 4 Gy

Genotype
MGI:3809981

cx3

• Allelic Composition: Nhej1^tm1Fwa/Nhej1^tm1Fwa; Trp53^tm1Tyj/Trp53^tm1Tyj
• Genetic Background: involves: 129

neoplasm

increased T cell derived lymphoma incidence ( J:138774 )

• 20 of 21 mice succumbed to thymic lymphoma with a media survival of 102.5 days

• lymphomas characterized lacked clonal translocations suggesting cancers arose from Trp53 deficiency alone

increased B cell derived lymphoma incidence ( J:138774 )

• 1 of 21 mice succumbed to pro-B cell lymphoma

• this lymphoma contained a clonal 12/15 translocation

increased medulloblastoma incidence ( J:138774 )

• necropsy on 8 mice that died from thymic lymphoma revealed 6 of these mice also had medulloblastomas in the brain

endocrine/exocrine glands

increased T cell derived lymphoma incidence ( J:138774 )

• 20 of 21 mice succumbed to thymic lymphoma with a media survival of 102.5 days

• lymphomas characterized lacked clonal translocations suggesting cancers arose from Trp53 deficiency alone

nervous system

increased medulloblastoma incidence ( J:138774 )

• necropsy on 8 mice that died from thymic lymphoma revealed 6 of these mice also had medulloblastomas in the brain

hematopoietic system

increased T cell derived lymphoma incidence ( J:138774 )

• 20 of 21 mice succumbed to thymic lymphoma with a media survival of 102.5 days

• lymphomas characterized lacked clonal translocations suggesting cancers arose from Trp53 deficiency alone

immune system

increased T cell derived lymphoma incidence ( J:138774 )

• 20 of 21 mice succumbed to thymic lymphoma with a media survival of 102.5 days

• lymphomas characterized lacked clonal translocations suggesting cancers arose from Trp53 deficiency alone

Genotype
MGI:5829791

cx4

• Allelic Composition: Nhej1^tm1Fwa/Nhej1^tm1Fwa; Xrcc5^tm1Nus/Xrcc5^tm1Nus
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6

Small body size, small spleen and absent thymus in Nhej1^tm1Fwa/Nhej1^tm1Fwa Xrcc5^tm1Nus/Xrcc5^tm1Nus mice

mortality/aging

mortality/aging ( J:236776 )

N • double homozygotes are born at the expected Mendelian frequencies and closely resemble single Xrcc5^tm1Nus homozygotes

growth/size/body

decreased body size ( J:236776 )

• at 8 weeks of age

immune system

athymia ( J:236776 )

• at 8 weeks of age

small spleen ( J:236776 )

• at 8 weeks of age

hematopoietic system

athymia ( J:236776 )

• at 8 weeks of age

small spleen ( J:236776 )

• at 8 weeks of age

endocrine/exocrine glands

athymia ( J:236776 )

• at 8 weeks of age

Genotype
MGI:6400579

cx5

• Allelic Composition: Cyren^{tm1.1(KOMP)Vlcg}/Cyren^{tm1.1(KOMP)Vlcg}; Nhej1^tm1Fwa/Nhej1^tm1Fwa
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6NTac

cellular

increased neuron apoptosis ( J:265834 )

• widespread neuronal apoptosis within cortex and ganglionic eminences at age E14.5-16.5

growth/size/body

decreased fetal size ( J:265834 )

• significantly reduced embryo size at age E14.5-16.5

mortality/aging

lethality throughout fetal growth and development, complete penetrance ( J:265834 )

• no mice born

• significantly reduced embryo size at age E14.5-16.5

• normal Mendelian ratio at age E14.5-16.5

nervous system

increased neuron apoptosis ( J:265834 )

• widespread neuronal apoptosis within cortex and ganglionic eminences at age E14.5-16.5

Genotype
MGI:5827971

cx6

• Allelic Composition: Paxx^em1Spj/Paxx^em1Spj; Nhej1^tm1Fwa/Nhej1^tm1Fwa
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6NTac

Small body size, absence of thymus, and small spleen in Paxx^em1Spj/Paxx^em1Spj Nhej1^tm1Fwa/Nhej1^tm1Fwa mice

mortality/aging

lethality throughout fetal growth and development, incomplete penetrance ( J:236776 )

• although double homozygotes are present at normal Mendelian frequencies at E14.5, a significant number of them are dead by E18.5

postnatal lethality, incomplete penetrance ( J:236776 )

• double homozygotes are severely underrepresented at 2 weeks of age, with only one mouse identified out of 25 expected

growth/size/body

decreased embryo size ( J:236776 )

• >50% of double mutant embryos are smaller than controls by E10.5

• however, somite numbers are normal at E10.5

decreased birth body size ( J:236776 )

• single born double mutant mouse is smaller than normal at birth

decreased body size ( J:236776 )

• single born double mutant mouse is smaller at 5 days of age and fails to thrive by 10 days of age

decreased body weight ( J:236776 )

• body weight of single born double mutant mouse is significantly reduced at 10 days of age

decreased fetal size ( J:236776 )

• double mutant fetuses are smaller than controls at E14.5

decreased fetal weight ( J:236776 )

• by E18.5, only a few double mutant fetuses are viable but show reduced body weight

immune system

athymia ( J:236776 )

• upon necropsy, single born double mutant mouse exhibited no thymus

abnormal thymus involution ( J:236776 )

• few double mutants surviving to E18.5 exhibit drastic involution of the thymus, unlike single Nhej1^tm1Fwa homozygotes

absent lymphocyte ( J:236776 )

• no lymphocytes are recovered upon red blood cell lysis

small spleen ( J:236776 )

• upon necropsy, single born double mutant mouse exhibited a microspleen

• few double mutants surviving to E18.5 exhibit much smaller spleens than controls

decreased spleen weight ( J:236776 )

• spleen weight of single born double mutant mouse is significantly reduced relative to body weight at 10 days of age

decreased splenocyte number ( J:236776 )

• single born double mutant mouse shows a significant decrease in splenic cell counts relative to body weight at 10 days of age

hematopoietic system

athymia ( J:236776 )

• upon necropsy, single born double mutant mouse exhibited no thymus

abnormal thymus involution ( J:236776 )

• few double mutants surviving to E18.5 exhibit drastic involution of the thymus, unlike single Nhej1^tm1Fwa homozygotes

absent lymphocyte ( J:236776 )

• no lymphocytes are recovered upon red blood cell lysis

small spleen ( J:236776 )

• upon necropsy, single born double mutant mouse exhibited a microspleen

• few double mutants surviving to E18.5 exhibit much smaller spleens than controls

decreased spleen weight ( J:236776 )

• spleen weight of single born double mutant mouse is significantly reduced relative to body weight at 10 days of age

decreased splenocyte number ( J:236776 )

• single born double mutant mouse shows a significant decrease in splenic cell counts relative to body weight at 10 days of age

cellular

increased neural tube apoptosis ( J:236776 )

• at E10.5 and E14.5, double mutants exhibit increased neural tube apoptosis, as shown by accumulation of cleaved caspase 3, especially in the cortical plate region of the cerebral cortex

• however, no increased apoptosis is observed in the skin, liver, heart or lung

chromosomal instability ( J:236776 )

• at E10.5 and E14.5, double mutants exhibit a significant increase in gammaH2AX-positive cells in the CNS (neural tube) relative to controls, indicating increased genomic instability

• mild genomic instability is also noted in the heart and skin

nervous system

increased neural tube apoptosis ( J:236776 )

• at E10.5 and E14.5, double mutants exhibit increased neural tube apoptosis, as shown by accumulation of cleaved caspase 3, especially in the cortical plate region of the cerebral cortex

• however, no increased apoptosis is observed in the skin, liver, heart or lung

embryo

decreased embryo size ( J:236776 )

• >50% of double mutant embryos are smaller than controls by E10.5

• however, somite numbers are normal at E10.5

endocrine/exocrine glands

athymia ( J:236776 )

• upon necropsy, single born double mutant mouse exhibited no thymus

abnormal thymus involution ( J:236776 )

• few double mutants surviving to E18.5 exhibit drastic involution of the thymus, unlike single Nhej1^tm1Fwa homozygotes