The PolgD257A 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 PolgD257A 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 (PolgD257A/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 PolgD257A/D257A tissues is observable by three months of age in the duodenum, liver, testes, and thymus.
Heterozygous mice (PolgD257A/+) also have an increased mutation burden, but no gross observable age-related phenotype, fertility problems, or other abnormalities are reported.
When PolgD257A mice are bred with Ins2Akita mice (Stock No. 003548), the double mutant offspring may be useful in studying appetite and diabetes.
