Phenotypes associated with this allele

• Allele Symbol: Ly6a^tm1Pmf
• Allele Name: targeted mutation 1, Patrick M Flood
• Allele ID: MGI:2449938
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Ly6a^tm1Pmf/Ly6a^tm1Pmf	B6.129P2-Ly6a^tm1Pmf	MGI:3815001
hm2	Ly6a^tm1Pmf/Ly6a^tm1Pmf	C.129P2-Ly6a^tm1Pmf	MGI:3815037
hm3	Ly6a^tm1Pmf/Ly6a^tm1Pmf	involves: 129P2/OlaHsd * C57BL/6	MGI:3815000
cx4	Kit^W-v/Kit^W-v Ly6a^tm1Pmf/Ly6a^tm1Pmf	involves: 129P2/OlaHsd * C57BL/6	MGI:3815027

Genotype
MGI:3815001

hm1

• Allelic Composition: Ly6a^tm1Pmf/Ly6a^tm1Pmf
• Genetic Background: B6.129P2-Ly6a^tm1Pmf

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

mortality/aging

mortality/aging ( J:42594 )

N • Background Sensitivity: homozygotes from early backcrosses to C57BL/6 are embryonic lethal

N • Background Sensitivity: this lethality is associated with a 129 D15Mit33 marker

N • Background Sensitivity: homozygotes carrying the C57BL/6 D15Mit33 marker are born at expected Mendelian frequences

immune system

abnormal T cell proliferation ( J:42594 )

• splenic T cells proliferate at a much higher rate when stimulated with Con-A

• mutant T cells have 156% of the response of wild-type T cells when stimulated with 2.0 micrograms/ml of Con A

• CD3 stimulation of T cells leads to a 3-fold greater proliferitave response than in wild-type T cells

• the percent increase in proliferation rates by mutant T cells over wild-type T cells is 159% at 48 h of CD3 stimulation, 272% at 72 h and 994% at 96 h

• T cells also have higer proliferative rates in mixed lymphocyte reactions ranging from 150- to 200% of the response of wild-type T cells

• T cells collected from mice challenged with KLH antigen have higher proliferative rates when stimulated with the KLH antigen, with responses ranging from 150% to 191% higher depending on concentration of KLH

• however, T cells do not increase their proliferative rate in the presence of anti-Ly6a antibody

• PMA with ionomycin activates T cells at similar levels as wild-type T cells

increased lymphocyte cell number ( J:81387 )

• lymphocytes make up 92.2% of white blood cells versus 90.57% in wild-type mice

abnormal myeloid leukocyte morphology ( J:81387 )

• CFU-GM, CFU-M, and CFU-G precursors are elevated in bone marrow

decreased granulocyte number ( J:81387 )

• granulocytes make up 2.11% of white blood cells versus 2.78% in wild-type mice

decreased monocyte cell number ( J:81387 )

• monocytes make up 5.69% of white blood cells versus 6.65% in wild-type mice

abnormal immunoglobulin level ( J:42594 )

• mice have lower serum concentrations of anti-KLH antibody after immunization with KLH, with responses ranging from 38 to 99% than in wild-typelower

hematopoietic system

abnormal T cell proliferation ( J:42594 )

• splenic T cells proliferate at a much higher rate when stimulated with Con-A

• mutant T cells have 156% of the response of wild-type T cells when stimulated with 2.0 micrograms/ml of Con A

• CD3 stimulation of T cells leads to a 3-fold greater proliferitave response than in wild-type T cells

• the percent increase in proliferation rates by mutant T cells over wild-type T cells is 159% at 48 h of CD3 stimulation, 272% at 72 h and 994% at 96 h

• T cells also have higer proliferative rates in mixed lymphocyte reactions ranging from 150- to 200% of the response of wild-type T cells

• T cells collected from mice challenged with KLH antigen have higher proliferative rates when stimulated with the KLH antigen, with responses ranging from 150% to 191% higher depending on concentration of KLH

• however, T cells do not increase their proliferative rate in the presence of anti-Ly6a antibody

• PMA with ionomycin activates T cells at similar levels as wild-type T cells

abnormal definitive hematopoiesis ( J:81387 )

• mutant bone marrow cells have a competitive disadvantage compared with wild-type bone marrow cells when used to replenish lethally irradiated wild-type mice

• lethally irradiated wild-type mice receiving transplants of bone marrow at a ratio of 2:1 mutant-to-wild-type cells showreconstitution by wild-type cells at more than twice the expected frequency

• mutant mice that received transplants consisting of 33% wild-type and mutant bone marrow cells have, on average, repopulation by 60% wild-type and 40% mutant cells

• bone marrow engraftment is severely reduced in serial transplantation of mutant bone marrow into irradiated wild-type mice with 33% of secondary transplantation hosts dying from irradiation-induced anemia

abnormal common myeloid progenitor cell morphology ( J:81387 )

• CFU numbers in the bone marrow are reduced by more than 60%

• CFU-spleen day-12 numbers are decreased by 38%

decreased megakaryocyte cell number ( J:81387 )

• bone marrow has a greater than 75% reduction in the number of megakaryocytes making up just 1.82% of the bone marrow compare to 7.42% in wild-type mice

thrombocytopenia ( J:81387 )

• platelet counts are greatly diminished from 1021.2 x 10 in wild-type mice to 615.5 x 10 in these mice

increased lymphocyte cell number ( J:81387 )

• lymphocytes make up 92.2% of white blood cells versus 90.57% in wild-type mice

abnormal myeloid leukocyte morphology ( J:81387 )

• CFU-GM, CFU-M, and CFU-G precursors are elevated in bone marrow

decreased granulocyte number ( J:81387 )

• granulocytes make up 2.11% of white blood cells versus 2.78% in wild-type mice

decreased monocyte cell number ( J:81387 )

• monocytes make up 5.69% of white blood cells versus 6.65% in wild-type mice

abnormal immunoglobulin level ( J:42594 )

• mice have lower serum concentrations of anti-KLH antibody after immunization with KLH, with responses ranging from 38 to 99% than in wild-typelower

homeostasis/metabolism

increased bleeding time ( J:81387 )

• bleeding time is increased by 69% compared to wild-type but the differences are not significant due to large variations within groups

cellular

abnormal T cell proliferation ( J:42594 )

• splenic T cells proliferate at a much higher rate when stimulated with Con-A

• mutant T cells have 156% of the response of wild-type T cells when stimulated with 2.0 micrograms/ml of Con A

• CD3 stimulation of T cells leads to a 3-fold greater proliferitave response than in wild-type T cells

• the percent increase in proliferation rates by mutant T cells over wild-type T cells is 159% at 48 h of CD3 stimulation, 272% at 72 h and 994% at 96 h

• T cells also have higer proliferative rates in mixed lymphocyte reactions ranging from 150- to 200% of the response of wild-type T cells

• T cells collected from mice challenged with KLH antigen have higher proliferative rates when stimulated with the KLH antigen, with responses ranging from 150% to 191% higher depending on concentration of KLH

• however, T cells do not increase their proliferative rate in the presence of anti-Ly6a antibody

• PMA with ionomycin activates T cells at similar levels as wild-type T cells

Genotype
MGI:3815037

hm2

• Allelic Composition: Ly6a^tm1Pmf/Ly6a^tm1Pmf
• Genetic Background: C.129P2-Ly6a^tm1Pmf

skeleton

abnormal osteoblast differentiation ( J:83409 )

• the number of ostoblast colony forming units cultured from bone marrow of 2-month old mice is half that of controls

• in vitro bone nodule formation is reduced by more than half in these bone marrow cultures

• committed osteoblast progenitors have a 7% increase in doubling time compared to controls

• the number of osteoblast progenitors isolated from bone marrow cultures is reduced

• however, the ratio of osteoblast progenitors to total number of stromal progenitors is the same

abnormal osteoclast differentiation ( J:83409 )

• osteoblast and splenic co-cultures generated less than 10% of the osteoclasts found in co-cultures of wild-type cells

• when mutant osteoblastic cells were used with wild-type splenocytes, markedly reduced numbers of wild-type osteoclasts are generated indicating a primary stromal cell defect in osteoclastogenesis

abnormal osteoblast physiology ( J:83409 )

• bone formation is essentially normal at 2 months of age but is dramatically reduced by 6 months of age

decreased osteoclast cell number ( J:83409 )

• the absolute number of osteoclasts is reduced by more than 40% in both 2- and 9- month old femurs

• osteoblast and splenic co-cultures generated less than 10% of the osteoclasts found in co-cultures of wild-type cells

decreased bone mineral content ( J:83409 )

• bone mineral content does not change between 2 months of age to 12 months of age while mineral content is increased in wild-type mice during this time period

decreased bone trabecula number ( J:83409 )

• femurs have 27% fewer trabeculae compared with control bones at 4 months of age and 58% compared with bones at 15 months of age

osteoporosis ( J:83409 )

• mice one year of age have the same bone mass density as 8 week old mice, which is significantly less than the bone mass of one year old wild-type mice

• the greatest decrease in bone mass density occurs in vertebrae

decreased osteoid volume ( J:83409 )

• the percent of osteoid in femurs are significantly lower in both 4- and 15- month old bones

decreased bone ossification ( J:83409 )

• bone formation is essentially normal at 2 months of age but is dramatically reduced by 6 months of age

decreased bone strength ( J:83409 )

• compression testing of 15-month old vertebrae shows the bone is not as stiff and is substantially weaker and more compliant than bones from wild-type animals

• the yield stress and failure stress of vertebrae are reduced by about a third while the elastic modulus is half that of controls

• femurs from 15-month-old mice have a similar stiffness to wild-type bones but are weaker and considerably more brittle

hematopoietic system

abnormal osteoclast differentiation ( J:83409 )

• osteoblast and splenic co-cultures generated less than 10% of the osteoclasts found in co-cultures of wild-type cells

• when mutant osteoblastic cells were used with wild-type splenocytes, markedly reduced numbers of wild-type osteoclasts are generated indicating a primary stromal cell defect in osteoclastogenesis

abnormal common myeloid progenitor cell morphology ( J:83409 )

• the total number of stromal progenitors found in bone marrow is reduced in 2- and 7- month old mice by 45% and 67%, respectively, compared to controls

• serial passaging of bone marrow stromal cultures reduces the number of stromal progenitors by more than half per passage, indicating a defect in self renewal

decreased osteoclast cell number ( J:83409 )

• the absolute number of osteoclasts is reduced by more than 40% in both 2- and 9- month old femurs

• osteoblast and splenic co-cultures generated less than 10% of the osteoclasts found in co-cultures of wild-type cells

adipose tissue

abnormal fat cell morphology ( J:83409 )

• bone marrow stroma contains two-thirds less adipocyte progenitors than controls

immune system

abnormal osteoclast differentiation ( J:83409 )

• osteoblast and splenic co-cultures generated less than 10% of the osteoclasts found in co-cultures of wild-type cells

• when mutant osteoblastic cells were used with wild-type splenocytes, markedly reduced numbers of wild-type osteoclasts are generated indicating a primary stromal cell defect in osteoclastogenesis

decreased osteoclast cell number ( J:83409 )

• the absolute number of osteoclasts is reduced by more than 40% in both 2- and 9- month old femurs

• osteoblast and splenic co-cultures generated less than 10% of the osteoclasts found in co-cultures of wild-type cells

cellular

abnormal osteoblast differentiation ( J:83409 )

• the number of ostoblast colony forming units cultured from bone marrow of 2-month old mice is half that of controls

• in vitro bone nodule formation is reduced by more than half in these bone marrow cultures

• committed osteoblast progenitors have a 7% increase in doubling time compared to controls

• the number of osteoblast progenitors isolated from bone marrow cultures is reduced

• however, the ratio of osteoblast progenitors to total number of stromal progenitors is the same

abnormal osteoclast differentiation ( J:83409 )

• osteoblast and splenic co-cultures generated less than 10% of the osteoclasts found in co-cultures of wild-type cells

• when mutant osteoblastic cells were used with wild-type splenocytes, markedly reduced numbers of wild-type osteoclasts are generated indicating a primary stromal cell defect in osteoclastogenesis

abnormal osteoblast physiology ( J:83409 )

• bone formation is essentially normal at 2 months of age but is dramatically reduced by 6 months of age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
osteoporosis		DOID:11476	OMIM:166710	J:83409

Genotype
MGI:3815000

hm3

• Allelic Composition: Ly6a^tm1Pmf/Ly6a^tm1Pmf
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

mortality/aging

prenatal lethality, complete penetrance ( J:42594 )

• Background Sensitivity: homozygotes from early backcrosses to C57BL/6 are embryonic lethal

• Background Sensitivity: this lethality is associated with a 129 D15Mit33 marker

• Background Sensitivity: homozygotes carrying a C57BL/6 D15Mit33 marker are not embryonic lethal and are born at expected Mendelian frequencies

Genotype
MGI:3815027

cx4

• Allelic Composition: Kit^W-v/Kit^W-v; Ly6a^tm1Pmf/Ly6a^tm1Pmf
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

mortality/aging

embryonic lethality, incomplete penetrance ( J:81387 )

• there is an 84% reduction in the number of compound homozygotes born compared to the number expected from Mendelian frequencies

hematopoietic system

abnormal common myeloid progenitor cell morphology ( J:81387 )

• E14 embryos have dramatically reduced CFU-Cs

anemia ( J:81387 )

• E14 embryos are very anemic