Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Inbred x Heterozygote         (Female x Male)   30-NOV-12 Mating System Heterozygote x Heterozygote         (Female x Male)   30-NOV-12 Species laboratory mouse Generation N16+pN1 (28-JAN-13) Generation Definitions   Donating Investigator Tomas A Prolla,   University of Wisconsin-Madison

Description
The Polg^D257A mutant allele has a mitochondrial DNA polymerase editing amino acid substitution, D257Am in the N-terminal "proofreading" exonuclease domain II of the DNA polymerase γ gene (Polg). The expressed mutant protein, Polg-D257A, lacks the polymerase proofreading function/mismatch repair mechanism in mitochondria (although mtDNA replication is not significantly altered). As such, homozygous Polg^D257A mice exhibit ~2500-fold increased rate of mtDNA mutation compared to wild-type mice. The accumulation of mtDNA mutations leads to increased apoptosis (particularly in cells/tissues that are metabolically active or have rapid cellular turnover). Homozygous (Polg^D257A/D257A) mice grossly demonstrate a premature aging phenotype beginning at ~nine months of age with alopecia, graying hair, impaired mobility and kyphosis, and die prematurely by ~13-15 months of age with severe anemia. Homozygous mice exhibit several age-related defects, including thymic involution, weight loss, testicular atrophy, and cardiac hypertrophy/dysfunction, as well as progressive loss of skeletal muscle (sarcopenia), bone mass, circulating red blood cells, hearing, and intestinal crypts. The testicular atrophy manifests around five months of age concurrent with depletion of spermatogonia. The cardiovascular phenotype includes macrocytic anemia with abnormal erythroid maturation and megaloblastic changes, as well as profound defects in lymphopoiesis (characteristics of human myelodysplastic syndromes). The hearing loss is attributed to cochlear hair cell degeneration (presbycusis), with onset around nine months of age. Histologically, increased apoptosis in Polg^D257A/D257A tissues is observable by three months of age in the duodenum, liver, testes, and thymus. Heterozygous mice (Polg^D257A/+) also have an increased mutation burden, but no gross observable age-related phenotype, fertility problems, or other abnormalities are reported.

When Polg^D257A mice are bred with Ins2^Akita mice (Stock No. 003548), the double mutant offspring may be useful in studying appetite and diabetes.

Development
To create the targeting vector, Dr. Tomas A. Prolla (University of Wisconsin, Madison) isolated a mouse DNA polymerase γ (Polg) DNA sequence and used site-directed mutagenesis to introduce an AC-->CT two-base substitution corresponding to positions 1054-1055 in exon 3. The targeting vector also had a loxP-flanked PGK-neo cassette inserted into intron 3. The point mutations create a D257A amino acid substitution in the conserved N-terminal "proofreading" exonuclease domain II of Polg. This targeting construct was electroporated into 129S7/SvEvBrd-Hprt^b-m2-derived AB2.2 embryonic stem (ES) cells, and correctly targeted ES cells were injected into blastocysts. Chimeric males were bred to C57BL/6J females. The PolgA^D257Aneo mice were then bred with CMV-Cre transgenic mice (on a mixed 129/ICR genetic background) to remove the floxed PGK-neo cassette. The resulting mice harboring the PolgA^D257A allele (also called Polg^D257A, Polg^mut, or Polg^A) were subsequently backcrossed 16 generations to C57BL/6J wildtype mice (and the CMV-Cre transgene was removed) prior to sending to The Jackson Laboratory Repository. Upon arrival, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Mitochondrial DNA Depletion Syndrome 4a (alpers Type); MTDPS4A   (POLG) Mitochondrial DNA Depletion Syndrome 4b (mngie Type); MTDPS4B   (POLG) Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions, Autosomal Dominant, 1; PEOA1   (POLG) Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions, Autosomal Recessive; PEOB   (POLG) Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoparesis; SANDO   (POLG)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Polg^tm1Tprol/Polg^tm1Tprol

        involves: 129S7/SvEvBrd * C57BL/6J * ICR

• mortality/aging
• premature aging
  • premature aging is seen at 9 months of age   (MGI Ref ID J:99764)
• premature death
  • maximum and median life span are reduced to 460 and 416 days, respectively   (MGI Ref ID J:99764)
• cellular phenotype
• abnormal mitochondrial physiology
  • by 9 months, homozygotes display increased mitochondrial DNA damage in the stria vascularis of the cochlea relative to age-matched wild-type mice   (MGI Ref ID J:119971)
• increased apoptosis
  • 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   (MGI Ref ID J:99764)
  • however, no increase in oxidative stress or cellular senescence are found   (MGI Ref ID J:99764)
• endocrine/exocrine gland phenotype
• abnormal crypts of Lieberkuhn morphology
  • age related loss of intestinal crypts   (MGI Ref ID J:99764)
• testicular atrophy
  • age related testicular atrophy begins at 5 months of age   (MGI Ref ID J:99764)
• growth/size phenotype
• weight loss
  • age-related weight loss   (MGI Ref ID J:99764)
• hearing/vestibular/ear phenotype
• cochlear hair cell degeneration
  • 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   (MGI Ref ID J:119971)
• • cochlear outer hair cell degeneration
    • 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   (MGI Ref ID J:119971)
• increased or absent threshold for auditory brainstem response
  • at 9 months, homozygotes display marked elevation of ABR thresholds at 4, 8, and 16 kHz relative to wild-type mice   (MGI Ref ID J:99764)
• increased susceptibility to age-related hearing loss   (MGI Ref ID J:99764)
  • 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   (MGI Ref ID J:119971)
  • in contrast, no significant ABR threshold elevations are observed at 2 months of age   (MGI Ref ID J:119971)
• stria vascularis degeneration
  • by 9 months, homozygotes exhibit strial degeneration, evidenced as vacuolar degeneration associated with mitochondrial damage   (MGI Ref ID J:119971)
• nervous system phenotype
• cochlear ganglion degeneration   (MGI Ref ID J:99764)
  • 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   (MGI Ref ID J:119971)
• cochlear hair cell degeneration
  • 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   (MGI Ref ID J:119971)
• • cochlear outer hair cell degeneration
    • 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   (MGI Ref ID J:119971)
• hematopoietic system phenotype
• abnormal thymus involution
  • thymus size and weight are reduced at 3 months of age   (MGI Ref ID J:99764)
• decreased erythrocyte cell number
  • age-related reduction in red blood cell numbers   (MGI Ref ID J:99764)
• immune system phenotype
• abnormal thymus involution
  • thymus size and weight are reduced at 3 months of age   (MGI Ref ID J:99764)
• muscle phenotype
• decreased skeletal muscle mass
  • age-related reduction in skeletal muscle mass seen by 9 months of age   (MGI Ref ID J:99764)
• skeleton phenotype
• kyphosis
  • age-related kyphosis   (MGI Ref ID J:99764)
• osteoporosis
  • age-related reduction in bone mass is seen earlier compared to wild-type mice   (MGI Ref ID J:99764)
• pigmentation phenotype
• abnormal coat/hair pigmentation
  • premature graying   (MGI Ref ID J:99764)
• reproductive system phenotype
• testicular atrophy
  • age related testicular atrophy begins at 5 months of age   (MGI Ref ID J:99764)
• digestive/alimentary phenotype
• abnormal crypts of Lieberkuhn morphology
  • age related loss of intestinal crypts   (MGI Ref ID J:99764)
• integument phenotype
• abnormal coat/hair pigmentation
  • premature graying   (MGI Ref ID J:99764)
• premature hair loss   (MGI Ref ID J:99764)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Apoptosis Research
Endogenous Regulators

Cancer Research
Genes Regulating Growth and Proliferation
Tumor Suppressor Genes

Cardiovascular Research
Heart Abnormalities
Vascular Defects

Cell Biology Research
DNA Damage Response
Genes Regulating Growth and Proliferation
Signal Transduction
Transcriptional Regulation

Dermatology Research
Skin and Hair Texture Defects

Developmental Biology Research
Internal/Organ Defects
      Lymphoid Tissue Defects
Lymphoid Tissue Defects
      hematopoietic defects
Skin and Hair Texture Defects

Hematological Research
Anemia, Iron Deficiency and Transport Defects
      macrocytic

Immunology, Inflammation and Autoimmunity Research
Lymphoid Tissue Defects
      hematopoietic development

Internal/Organ Research
Lymphoid Tissue Defects
Thymus Defects

Neurobiology Research
Ataxia (Movement) Defects
Hearing Defects
      Age related hearing loss

Reproductive Biology Research
Developmental Defects Affecting Gonads
      males only
Fertility Defects
      males only

Research Tools
Apoptosis Research
Cardiovascular Research
Reproductive Biology Research
      male germ cells

Sensorineural Research
Hearing Defects
      Age related hearing loss

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Polgtm1Tprol
Allele Name		targeted mutation 1, T A Prolla
Allele Type		Targeted (knock-in)
Common Name(s)		PolgA; Polgm; Polgmut; PolgAD257A;
Mutation Made By		Tomas Prolla,   University of Wisconsin-Madison
Strain of Origin		129S7/SvEvBrd-Hprt
Promoter		Polg, polymerase (DNA directed), gamma, mouse, laboratory
Molecular Note		A targeting construct was designed to introduce an AC to CT two-base substitution in positions 1054 and 1055, resulting in a critical residue substitution in the conserved exonuclease domain. [MGI Ref ID J:99764]

Genotyping

Genotyping Information

Genotyping Protocols

Polg^tm1Tprol, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Chen ML; Logan TD; Hochberg ML; Shelat SG; Yu X; Wilding GE; Tan W; Kujoth GC; Prolla TA; Selak MA; Kundu M; Carroll M; Thompson JE. 2009. Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction. Blood 114(19):4045-53. [PubMed: 19734452]  [MGI Ref ID J:154187]

Fox R; Kim HS; Reddick RL; Kujoth GC; Prolla TA; Tsutsumi S; Wada Y; Smithies O; Maeda N. 2011. Mitochondrial DNA polymerase editing mutation, PolgD257A, reduces the diabetic phenotype of Akita male mice by suppressing appetite. Proc Natl Acad Sci U S A 108(21):8779-84. [PubMed: 21555558]  [MGI Ref ID J:171899]

Hiona A; Sanz A; Kujoth GC; Pamplona R; Seo AY; Hofer T; Someya S; Miyakawa T; Nakayama C; Samhan-Arias AK; Servais S; Barger JL; Portero-Otin M; Tanokura M; Prolla TA; Leeuwenburgh C. 2010. Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice. PLoS One 5(7):e11468. [PubMed: 20628647]  [MGI Ref ID J:163116]

Kujoth GC; Hiona A; Pugh TD; Someya S; Panzer K; Wohlgemuth SE; Hofer T; Seo AY; Sullivan R; Jobling WA; Morrow JD; Van Remmen H; Sedivy JM; Yamasoba T; Tanokura M; Weindruch R; Leeuwenburgh C; Prolla TA. 2005. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309(5733):481-4. [PubMed: 16020738]  [MGI Ref ID J:99764]

Vermulst M; Bielas JH; Kujoth GC; Ladiges WC; Rabinovitch PS; Prolla TA; Loeb LA. 2007. Mitochondrial point mutations do not limit the natural lifespan of mice. Nat Genet 39(4):540-3. [PubMed: 17334366]  [MGI Ref ID J:141666]

Additional References

Polg^tm1Tprol related

Chen H; Vermulst M; Wang YE; Chomyn A; Prolla TA; McCaffery JM; Chan DC. 2010. Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 141(2):280-9. [PubMed: 20403324]  [MGI Ref ID J:167952]

Dai DF; Johnson SC; Villarin JJ; Chin MT; Nieves-Cintron M; Chen T; Marcinek DJ; Dorn GW 2nd; Kang YJ; Prolla TA; Santana LF; Rabinovitch PS. 2011. Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circ Res 108(7):837-46. [PubMed: 21311045]  [MGI Ref ID J:183593]

Fox RG; Magness S; Kujoth GC; Prolla TA; Maeda N. 2012. Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption. Am J Physiol Gastrointest Liver Physiol 302(9):G914-24. [PubMed: 22345551]  [MGI Ref ID J:187490]

Jang YC; Remmen VH. 2009. The mitochondrial theory of aging: insight from transgenic and knockout mouse models. Exp Gerontol 44(4):256-60. [PubMed: 19171187]  [MGI Ref ID J:146518]

Safdar A; Bourgeois JM; Ogborn DI; Little JP; Hettinga BP; Akhtar M; Thompson JE; Melov S; Mocellin NJ; Kujoth GC; Prolla TA; Tarnopolsky MA. 2011. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proc Natl Acad Sci U S A 108(10):4135-40. [PubMed: 21368114]  [MGI Ref ID J:170832]

Someya S; Yamasoba T; Kujoth GC; Pugh TD; Weindruch R; Tanokura M; Prolla TA. 2008. The role of mtDNA mutations in the pathogenesis of age-related hearing loss in mice carrying a mutator DNA polymerase gamma. Neurobiol Aging 29(7):1080-92. [PubMed: 17363114]  [MGI Ref ID J:140916]

Yamasoba T; Someya S; Yamada C; Weindruch R; Prolla TA; Tanokura M. 2007. Role of mitochondrial dysfunction and mitochondrial DNA mutations in age-related hearing loss. Hear Res 226(1-2):185-93. [PubMed: 16870370]  [MGI Ref ID J:119971]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           MGL375/377

Colony Maintenance

Breeding & Husbandry	Both heterozygous and homozygous mice have progressive accumulation of mtDNA point mutations. Considering that paternal mitochondrial DNA is actively eliminated following fertilization in mice, one can minimize the (undesirable) accumulation of these mutations in the germline by breeding wildtype females or C57BL/6J inbred females (Stock No. 000664) with heterozygous males.
Mating System	Inbred x Heterozygote         (Female x Male)   30-NOV-12
	Heterozygote x Heterozygote         (Female x Male)   30-NOV-12

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

 

This strain is currently Under Development - Now Accepting Orders.
Estimated Available for Distribution Date: 30-SEP-13

Please note: You may now place orders for this strain although it is not yet ready for distribution. Estimated available for distribution dates are provided to keep customers better informed on strains under development. Please note that our Colony Managers routinely monitor the target date and edit it based on breeding performance and other factors. The length of time it takes to make a new strain available for distribution depends on genotype, age, number of animals sent by the Donating Investigator, breeding performance, additional strain development (backcrossing, making homozygous), and anticipated demand for the strain.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

See Terms of Use tab for General Terms and Conditions

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

---

Ordering Information
JAX^® Mice
Surgical and Preconditioning Services
JAX^® Services
Customer Services and Support
Tel: 1-800-422-6423 or 1-207-288-5845
Fax: 1-207-288-6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

For Licensing and Use Restrictions view the link(s) below:
- Use of MICE by companies or for-profit entities requires a license prior to shipping.

Contact information

General inquiries regarding Terms of Use

Contracts Administration

phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice, Products & Services Conditions of Use

"MICE" means mouse strains, their progeny derived by inbreeding or crossbreeding, unmodified derivatives from mouse strains or their progeny supplied by The Jackson Laboratory ("JACKSON"). "PRODUCTS" means biological materials supplied by JACKSON, and their derivatives. "RECIPIENT" means each recipient of MICE, PRODUCTS, or services provided by JACKSON including each institution, its employees and other researchers under its control. MICE or PRODUCTS shall not be: (i) used for any purpose other than the internal research, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services. Acceptance of MICE or PRODUCTS from JACKSON shall be deemed as agreement by RECIPIENT to these conditions, and departure from these conditions requires JACKSON's prior written authorization.

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of mice, products or services, JACKSON will, at its option, provide credit or replacement for the mice or product received or the services provided.

No Liability

In no event shall JACKSON, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, PRODUCTS or services, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of JACKSON, its agents or employees. Unless prohibited by law, in purchasing or receiving MICE, PRODUCTS or services from JACKSON, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges JACKSON from all such causes of action or damages, and further agrees to defend and indemnify JACKSON from any costs or damages arising out of any third party claims.

MICE and PRODUCTS are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to JACKSON’s MICE, PRODUCTS or services. In addition, special terms and conditions of sale of certain MICE, PRODUCTS or services may be set forth separately in JACKSON web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, PRODUCTS and services by JACKSON, and by its licensees and distributors.

Acceptance of delivery of MICE, PRODUCTS or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on JACKSON, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, PRODUCTS or services by JACKSON.