Phenotypes associated with this allele

• Allele Symbol: Gt(ROSA)26Sor^{tm1(CAG-SETBP1*G870S,-EGFP)Ase}
• Allele Name: targeted mutation 1, Alessandro Sessa
• Allele ID: MGI:8207504
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Gt(ROSA)26Sor^tm1(CAG-SETBP1*G870S,-EGFP)Ase/Gt(ROSA)26Sor^+ Tg(CMV-cre)1Cgn/0	involves: BALB/cJ * C57BL/6J	MGI:8209436
cn2	Gt(ROSA)26Sor^tm1(CAG-SETBP1*G870S,-EGFP)Ase/Gt(ROSA)26Sor^+ Tg(Nes-cre)1Kln/0	involves: C57BL/6 * C57BL/6J * SJL	MGI:8209433
cn3	Gt(ROSA)26Sor^tm1(CAG-SETBP1*G870S,-EGFP)Ase/Gt(ROSA)26Sor^+ Commd10^Tg(Vav1-icre)A2Kio/Commd10^+	involves: C57BL/6N * C57BL/10 * CBA/Ca	MGI:8209199
cn4	Gt(ROSA)26Sor^tm1(CAG-SETBP1*G870S,-EGFP)Ase/Gt(ROSA)26Sor^tm1(CAG-SETBP1*G870S,-EGFP)Ase Commd10^Tg(Vav1-icre)A2Kio/Commd10^+	involves: C57BL/6N * C57BL/10 * CBA/Ca	MGI:8209200

Genotype
MGI:8209436

cn1

• Allelic Composition: Gt(ROSA)26Sor^{tm1(CAG-SETBP1*G870S,-EGFP)Ase}/Gt(ROSA)26Sor⁺; Tg(CMV-cre)1Cgn/0
• Genetic Background: involves: BALB/cJ * C57BL/6J

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

mortality/aging

embryonic lethality prior to tooth bud stage, complete penetrance ( J:363042 )

• no embryos are obtained at E12.5 or E14.5

embryo

embryonic growth retardation ( J:363042 )

• E9.5-E10.5 embryos are underdeveloped

growth/size/body

embryonic growth retardation ( J:363042 )

• E9.5-E10.5 embryos are underdeveloped

hematopoietic system

abnormal embryonic erythrocyte morphology ( J:363042 )

• embryos exhibit a reduced content of mature CD71+Ter119+ primitive erythrocytes within the yolk sac vascular plexus

Genotype
MGI:8209433

cn2

• Allelic Composition: Gt(ROSA)26Sor^{tm1(CAG-SETBP1*G870S,-EGFP)Ase}/Gt(ROSA)26Sor⁺; Tg(Nes-cre)1Kln/0
• Genetic Background: involves: C57BL/6 * C57BL/6J * SJL

nervous system

abnormal neuron differentiation ( J:363042 )

• E14.5 embryos show slow development in the cortex, where apical radial glial cells (RGCs; SOX2+) tend to accumulate at the expense of committed intermediate neural progenitors (INPs; TBR2+) and early differentiating neurons (DCX+)

abnormal radial glial cell morphology ( J:363042 )

• cortical radial glial cells exhibit a simpler neuronal shape

increased radial glial cell number ( J:363042 )

• apical radial glial cells (RGCs; SOX2+) tend to accumulate in the cortex in E14.5 embryos

abnormal brain morphology ( J:363042 )

• P30 mice exhibit reduced brain structure (e.g. cortical wall)

abnormal brain ventricle morphology ( J:363042 )

• P30 mice exhibit increased ventricle volume

growth/size/body

microcephaly ( J:363042 )

• P30 mice exhibit microcephaly

cellular

abnormal neuron differentiation ( J:363042 )

• E14.5 embryos show slow development in the cortex, where apical radial glial cells (RGCs; SOX2+) tend to accumulate at the expense of committed intermediate neural progenitors (INPs; TBR2+) and early differentiating neurons (DCX+)

abnormal radial glial cell morphology ( J:363042 )

• cortical radial glial cells exhibit a simpler neuronal shape

increased radial glial cell number ( J:363042 )

• apical radial glial cells (RGCs; SOX2+) tend to accumulate in the cortex in E14.5 embryos

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Schinzel Giedion syndrome		DOID:0070509	OMIM:269150	J:363042

Genotype
MGI:8209199

cn3

• Allelic Composition: Gt(ROSA)26Sor^{tm1(CAG-SETBP1*G870S,-EGFP)Ase}/Gt(ROSA)26Sor⁺; Commd10^{Tg(Vav1-icre)A2Kio}/Commd10⁺
• Genetic Background: involves: C57BL/6N * C57BL/10 * CBA/Ca

mortality/aging

premature death ( J:363041 )

• median survival of 108 days

• 100% of mice succumb of multiorgan failure due to extreme leukocytosis

behavior/neurological

lethargy ( J:363041 )

• moribund mice appear lethargic

growth/size/body

hepatosplenomegaly ( J:363041 )

hematopoietic system

abnormal hematopoietic system morphology/development ( J:363041 )

• mice show signs of hematological disease between 30 and 90 days after birth, developing a myeloproliferative neoplasm (MPN) disease characterized by myelofibrosis, megakaryocytic-restricted dysplasia, marked mature leukocytosis, and progressive splenomegaly

increased common myeloid progenitor cell number ( J:363041 )

• bone marrow shows an expansion of common myeloid progenitors (CMPs)

extramedullary hematopoiesis ( J:363041 )

• clusters of variably segmented myeloid cells accumulate in the liver and in the red pulp of the spleen indicating extramedullary hematopoiesis

anemia ( J:363041 )

• anemia is exacerbated in lethally irradiated syngenic recipients receiving bone marrow cells from mutant doners and transplanted mice die within 16 days after transplant because of extreme anemia

• mild anemia is seen in sublethally irradiated syngenic recipients receiving bone marrow cells from mutant doners and all transplanted mice develop an accelerated form of chronic myeloproliferation

abnormal bone marrow cell number ( J:363041 )

• bone marrow shows an expansion of lineage-negative (Lin-) cells

abnormal megakaryocyte morphology ( J:363041 )

• atypical megakaryocytes are commonly seen in the bone marrow, with frequent hypolobulated bulbous nuclei, dark chromatin with irregular borders, and folding of the nuclear surface

thrombocytopenia ( J:363041 )

• peripheral blood shows lower platelet counts

• thrombocytopenia is exacerbated in lethally irradiated syngenic recipients receiving bone marrow cells from mutant doners

decreased lymphocyte cell number ( J:363041 )

increased leukocyte cell number ( J:363041 )

• 100% of mice succumb of multiorgan failure due to extreme leukocytosis

• massive leukocytosis is seen in sublethally irradiated syngenic recipients receiving bone marrow cells from mutant doners and all transplanted mice develop an accelerated form of chronic myeloproliferation

increased myeloid cell number ( J:363041 )

• peripheral blood shows an imbalance between the lymphoid and myeloid lineages in favor of the latter, with an increase of mature myeloid cells and a reduction in the percentage of lymphocytes

• -however, no evidence of granulocytic dysplasia is seen and no circulating blasts or nonsegmented myeloid precursors are seen in the peripheral blood

myeloid hyperplasia ( J:363041 )

• bone marrow shows overt myeloid hyperplasia with no evidence of dysplasia except for the megakaryotic lineage

decreased hematopoietic stem cell number ( J:363041 )

• within the Lin- population, the fraction of multipotent Lin-/Sca1+/c-Kit+ (LSK) cells is reduced and very few hematopoietic stem cells (HSCs; CD150+/CD48-) are seen

• however, no change in the MPP fraction (CD150-/CD48+) is seen

abnormal spleen morphology ( J:363041 )

• spleen shows distortion of the normal architecture

• spleen shows massive infiltration by mature myeloid cells and a loss of lymphoid cells

• spleen shows an aberrantly large Lin- population, with a significant fraction being c-Kit+/Sca1-, suggesting a myeloid progenitor phenotype

hepatosplenomegaly ( J:363041 )

immune system

myeloid hyperplasia ( J:363041 )

• bone marrow shows overt myeloid hyperplasia with no evidence of dysplasia except for the megakaryotic lineage

decreased lymphocyte cell number ( J:363041 )

increased leukocyte cell number ( J:363041 )

• 100% of mice succumb of multiorgan failure due to extreme leukocytosis

• massive leukocytosis is seen in sublethally irradiated syngenic recipients receiving bone marrow cells from mutant doners and all transplanted mice develop an accelerated form of chronic myeloproliferation

abnormal spleen morphology ( J:363041 )

• spleen shows distortion of the normal architecture

• spleen shows massive infiltration by mature myeloid cells and a loss of lymphoid cells

• spleen shows an aberrantly large Lin- population, with a significant fraction being c-Kit+/Sca1-, suggesting a myeloid progenitor phenotype

hepatosplenomegaly ( J:363041 )

liver/biliary system

abnormal liver morphology ( J:363041 )

• liver shows distortion of the normal architecture

hepatosplenomegaly ( J:363041 )

skeleton

myelofibrosis ( J:363041 )

• adult mice show stromal changes with reticulin fibrosis in the bone marrow

• bone marrow shows an increased network of reticulin fibers with many intersections, with a predominant peritrabecular distribution but also extending within the intertrabecular spaces, and the presence of thick, confluent collagen fibers

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
myelofibrosis		DOID:4971	OMIM:254450	J:363041

Genotype
MGI:8209200

cn4

• Allelic Composition: Gt(ROSA)26Sor^{tm1(CAG-SETBP1*G870S,-EGFP)Ase}/Gt(ROSA)26Sor^{tm1(CAG-SETBP1*G870S,-EGFP)Ase}; Commd10^{Tg(Vav1-icre)A2Kio}/Commd10⁺
• Genetic Background: involves: C57BL/6N * C57BL/10 * CBA/Ca

mortality/aging

premature death ( J:363041 )

• mice have dramatically decreased overall survival with a median survival of 51 days

hematopoietic system

abnormal myelopoiesis ( J:363041 )

• mice develop myeloid disease with shorter latency than in heterozygotes

increased neutrophil cell number ( J:363041 )

• mice exhibit massive neutrophilia that is evident at 30 days of age

decreased leukocyte cell number ( J:363041 )

• mice exhibit lymphopenia that is evident at 30 days of age

immune system

abnormal myelopoiesis ( J:363041 )

• mice develop myeloid disease with shorter latency than in heterozygotes

increased neutrophil cell number ( J:363041 )

• mice exhibit massive neutrophilia that is evident at 30 days of age

decreased leukocyte cell number ( J:363041 )

• mice exhibit lymphopenia that is evident at 30 days of age

neoplasm

increased acute myeloid leukemia incidence ( J:363041 )

• in approximately 20% of mice, extramedullary masses of myeloid blasts are seen at autopsy, suggesting progression to an acute leukemia