Phenotypes associated with this allele

• Allele Symbol: Polg^tm1Prol
• Allele Name: targeted mutation 1, Tomas A Prolla
• Allele ID: MGI:3583920
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Polg^tm1Prol/Polg^tm1Prol	B6J.129S7-Polg^tm1Prol	MGI:5637428
hm2	Polg^tm1Prol/Polg^tm1Prol	involves: 129S7/SvEvBrd * C57BL/6J * ICR	MGI:3584104

Genotype
MGI:5637428

hm1

• Allelic Composition: Polg^tm1Prol/Polg^tm1Prol
• Genetic Background: B6J.129S7-Polg^tm1Prol

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

mortality/aging

premature death ( J:154187 )

• mice die by 15 months of age

hematopoietic system

abnormal lymphopoiesis ( J:154187 )

• abnormal lymphoid development in aging mice

decreased immature B cell number ( J:154187 )

• 8-13 month old mice show defects in the generation of immature B/pre-B cells

decreased pro-B cell number ( J:154187 )

• 8-13 month old mice show defects in the generation of pro-B cells

decreased double-positive T cell number ( J:154187 )

• decrease in the relative frequency of CD4/CD8 double-positive cells in 8-13 month old mice

macrocytic anemia ( J:154187 )

• macrocytic anemia appears as early as 6 months of age and progressively worsens

• transplantation of mutant marrow into wild-type recipients recapitulates age-related macrocytic anemia, lymphopenia, and megaloblastic changes

decreased lymphocyte cell number ( J:154187 )

• mice become lymphopenic by 8 months of age, involving both major lymphoid lineages

• however, mice do not develop leukocytosis or signs of leukemic conversion

decreased thymocyte number ( J:154187 )

• decrease in total viable thymocytes in 8-13 month old mice

decreased mature B cell number ( J:154187 )

• bone marrow of 8-13 month old mice shows a decrease in mature B cells

decreased pre-B cell number ( J:154187 )

• 8-13 month old mice show defects in the generation of immature B/pre-B cells

abnormal erythroid lineage cell morphology ( J:154187 )

• abnormal erythroid development in aging mice

• 8 month old mice exhibit an increase in the frequency of Ter119+ splenocytes, with a significant expansion in both polychromatophilic normoblasts and reticulocytes

• 10 month old splenocytes exhibit stress erythropoiesis, with a significant increase in frequency of polychromatophilic normoblasts

• in the bone marrow of 10 month old mice, an expansion of polychormatophilic normoblasts is seen at the expense of both reticulocytes and mature red blood cells

increased erythroblast number ( J:154187 )

• 8 and 10 month old splenocytes and 10 month old bone marrow show an increase in the frequency of polychromatophilic normoblasts

• a population of erythroblasts characterized by intermediate cell size and low-to-negative expression of CD71 is expanded in the bone marrow of 10 month old mice; this population of orthochromic erythroblasts has abundant, fully hemoglobinized cytoplasm, indicating megoblastic morphologic changes

decreased hemoglobin content ( J:154187 )

• from 6 to 10 months of age, hemoglobin levels are moderately decreased and from 11 months onward, hemoglobin levels rapidly decrease

increased mean corpuscular volume ( J:154187 )

• mean corpuscular volume of reticulocytes increases sharply from 8 months of age

macrocytosis ( J:154187 )

• macrocytosis becomes evident after 8 months of age, shortly after development of anemia, and worsens with age

cellular

abnormal mitochondrial physiology ( J:154187 )

• as early as 4 months of age, a decreased cytochrome oxidase/citrate synthase ratio is seen in mitochondria of the spleen and this ratio is decreased in both spleen and liver mitochondria at 9-10 months of age, indicating mitochondrial dysfunction

endocrine/exocrine glands

decreased thymocyte number ( J:154187 )

• decrease in total viable thymocytes in 8-13 month old mice

immune system

abnormal lymphopoiesis ( J:154187 )

• abnormal lymphoid development in aging mice

decreased immature B cell number ( J:154187 )

• 8-13 month old mice show defects in the generation of immature B/pre-B cells

decreased pro-B cell number ( J:154187 )

• 8-13 month old mice show defects in the generation of pro-B cells

decreased double-positive T cell number ( J:154187 )

• decrease in the relative frequency of CD4/CD8 double-positive cells in 8-13 month old mice

decreased lymphocyte cell number ( J:154187 )

• mice become lymphopenic by 8 months of age, involving both major lymphoid lineages

• however, mice do not develop leukocytosis or signs of leukemic conversion

decreased thymocyte number ( J:154187 )

• decrease in total viable thymocytes in 8-13 month old mice

decreased mature B cell number ( J:154187 )

• bone marrow of 8-13 month old mice shows a decrease in mature B cells

decreased pre-B cell number ( J:154187 )

• 8-13 month old mice show defects in the generation of immature B/pre-B cells

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
myelodysplastic syndrome		DOID:0050908	OMIM:614286	J:154187

Genotype
MGI:3584104

hm2

• Allelic Composition: Polg^tm1Prol/Polg^tm1Prol
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6J * ICR

mortality/aging

premature death ( J:99764 )

• maximum and median life span are reduced to 460 and 416 days, respectively

premature aging ( J:99764 )

• premature aging is seen at 9 months of age

cellular

increased apoptosis ( J:99764 )

• levels of cleaved caspase-3 and TUNEL staining are increased at 3 months of age in the duodenum, liver, testes, and thymus and levels of cleaved caspase-3 are increased in the skeletal muscle at 9 months of age

• however, no increase in oxidative stress or cellular senescence are found

abnormal mitochondrial physiology ( J:119971 )

• by 9 months, homozygotes display increased mitochondrial DNA damage in the stria vascularis of the cochlea relative to age-matched wild-type mice

endocrine/exocrine glands

abnormal crypts of Lieberkuhn morphology ( J:99764 )

• age related loss of intestinal crypts

testicular atrophy ( J:99764 )

♂ • age related testicular atrophy begins at 5 months of age

abnormal thymus involution ( J:99764 )

• thymus size and weight are reduced at 3 months of age

growth/size/body

weight loss ( J:99764 )

• age-related weight loss

hearing/vestibular/ear

cochlear hair cell degeneration ( J:119971 )

• by 9 months, homozygotes display significantly greater loss of cochlear hair cells (esp. OHCs) in the basal turn of the cochlea relative to age-matched wild-type mice or 2-mo-old homozygotes

cochlear outer hair cell degeneration ( J:119971 )

• by 9 months, homozygotes display significant loss of OHCs in the basal cochlear turn relative to age-matched wild-type mice or 2-mo-old homozygotes

stria vascularis degeneration ( J:119971 )

• by 9 months, homozygotes exhibit strial degeneration, evidenced as vacuolar degeneration associated with mitochondrial damage

increased or absent threshold for auditory brainstem response ( J:99764 )

• at 9 months, homozygotes display marked elevation of ABR thresholds at 4, 8, and 16 kHz relative to wild-type mice

increased susceptibility to age-related hearing loss ( J:99764 , J:119971 )

• by 9 months of age, homozygotes display significantly elevated ABR thresholds at all test frequencies (4, 8, and 16 kHz) relative to wild-type mice (J:119971)

• in contrast, no significant ABR threshold elevations are observed at 2 months of age (J:119971)

nervous system

cochlear hair cell degeneration ( J:119971 )

• by 9 months, homozygotes display significantly greater loss of cochlear hair cells (esp. OHCs) in the basal turn of the cochlea relative to age-matched wild-type mice or 2-mo-old homozygotes

cochlear outer hair cell degeneration ( J:119971 )

• by 9 months, homozygotes display significant loss of OHCs in the basal cochlear turn relative to age-matched wild-type mice or 2-mo-old homozygotes

cochlear ganglion degeneration ( J:99764 , J:119971 )

• by 9 months, homozygotes display significantly greater loss of spiral ganglion neurons in the lower basal turn of the cochlea relative to age-matched wild-type mice or 2-mo-old homozygotes (J:119971)

hematopoietic system

abnormal thymus involution ( J:99764 )

• thymus size and weight are reduced at 3 months of age

decreased erythrocyte cell number ( J:99764 )

• age-related reduction in red blood cell numbers

immune system

abnormal thymus involution ( J:99764 )

• thymus size and weight are reduced at 3 months of age

muscle

decreased skeletal muscle mass ( J:99764 )

• age-related reduction in skeletal muscle mass seen by 9 months of age

skeleton

kyphosis ( J:99764 )

• age-related kyphosis

osteoporosis ( J:99764 )

• age-related reduction in bone mass is seen earlier compared to wild-type mice

pigmentation

abnormal coat/hair pigmentation ( J:99764 )

• premature graying

reproductive system

testicular atrophy ( J:99764 )

♂ • age related testicular atrophy begins at 5 months of age

digestive/alimentary system

abnormal crypts of Lieberkuhn morphology ( J:99764 )

• age related loss of intestinal crypts

integument

abnormal coat/hair pigmentation ( J:99764 )

• premature graying

premature hair loss ( J:99764 )