Ampd2 homozygous knock-out mice show deviations in nucleotide metabolism and develop proteinuria. When combined with an Ampd3 knock-out (Ampd3tm2a(KOMP)Wtsi, available from the KOMP Repository), a neurodegenerative phenotype is seen.
Joseph G Gleeson, University of California, San Diego
Takayuki Morisaki, National Cerebral and Cardiovascular Center Research Institute
Ampd2 (adenosine monophosphate deaminase 2) plays a role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. Mutations in the gene have been associated with pontocerebellar hypoplasia (PCH), a rare, inherited, progressive neurodegenerative disorder with prenatal onset that is associated with a loss of brainstem and cerebellar parenchyma.
Mice homozygous for this Ampd2 knock-out allele show no histological neuronal phenotype, and are viable and fertile. A significant increase in AMP and decrease in ATP and GTP are observed in the kidneys of knockout mice at 12-24 weeks of age. In addition to changes in nucleotide metabolism in the kidneys, proteinuria is discernable at 3 weeks of age, increasing to transient peak levels at 6 weeks of age. Ultrastructural studies of glomerular specimens show effacement of the podocyte processes, resembling minimal-change nephropathy in humans.
Pups homozygous for both this Ampd2 mutation and a knock-out of Ampd3 (Ampd3tm2a(KOMP)Wtsi, available from the KOMP Repository) are born in the expected Mendelian ratio, but show slightly reduced body weight and have a severely shortened lifespan. Most die by postnatal day 21. Although the brain of newborns is slightly reduced in size, double knock-out mice show little evidence of the characteristic neuronal loss observed in AMPD2 mutant patients. A neurodegenerative phenotype is observed, mostly affecting the CA3 pyramidal neurons in the hippocampus and some sparse pyknotic cells all over the cortex and cerebellum. This is associated with a behavioral gait disturbance after postnatal day 10. Brains of 2 week old double knock-out animals show a 25% increase in ATP nucleotide levels and a 33% decrease in GTP levels, as compared to wildtype.
Exons 15 and 16, encoding catalytic activity sites, were replaced with a PGK-puromycin resistance cassette via homologous recombination in 129S2/SvPas-derived D3 embryonic stem (ES) cells. Resultant chimeric males were bred to C57BL/6J females. This strain was backcrossed to C57BL/6 for more than 10 generations.
|Allele Name||targeted mutation 1, Takayuki Morisaki|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Ampd2, adenosine monophosphate deaminase 2|
|Strain of Origin||129S2/SvPas|
|Molecular Note||A puro cassette replaced exons 15 and 16. Western blot analysis confirmed the absence of protein expression in the liver, kidney, lung, spleen, testis and brain.|
Heterozygotes and homozygotes are viable and fertile.
When using the B6.129S2-Ampd2tm1Tm/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #024913 in your Materials and Methods section.