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An N-ethyl-N-nitrosourea (ENU)-induced Tyr265Stop mutation of the DNA polymerase accessory subunit gamma 2 (Polg2) is associated with renal calcification in mice

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Item Type:Article
Title:An N-ethyl-N-nitrosourea (ENU)-induced Tyr265Stop mutation of the DNA polymerase accessory subunit gamma 2 (Polg2) is associated with renal calcification in mice
Creators Name:Gorvin, C.M., Ahmad, B.N., Stechman, M.J., Loh, N.Y., Hough, T.A., Leo, P., Marshall, M., Sethi, S., Bentley, L., Piret, S.E., Reed, A., Jeyabalan, J., Christie, P.T., Wells, S., Simon, M.M., Mallon, A.M., Schulz, H., Huebner, N., Brown, M.A., Cox, R.D., Brown, S.D. and Thakker, R.V.
Abstract:Renal calcification (RCALC) resulting in nephrolithiasis and nephrocalcinosis, which affects approximately 10% of adults by 70 years of age, involves environmental and genetic etiologies. Thus, nephrolithiasis and nephrocalcinosis occurs as an inherited disorder in approximately 65% of patients, and may be associated with endocrine and metabolic disorders including: primary hyperparathyroidism, hypercalciuria, renal tubular acidosis, cystinuria, and hyperoxaluria. Investigations of families with nephrolithiasis and nephrocalcinosis have identified some causative genes, but further progress is limited as large families are unavailable for genetic studies. We therefore embarked on establishing mouse models for hereditary nephrolithiasis and nephrocalcinosis by performing abdominal X-rays to identify renal opacities in N-ethyl-N-nitrosourea (ENU)-mutagenized mice. This identified a mouse with RCALC inherited as an autosomal dominant trait, designated RCALC type 2 (RCALC2). Genome-wide mapping located the Rcalc2 locus to a approximately 16Mbp region on chromosome 11D-E2 and whole-exome sequence analysis identified a heterozygous mutation in the DNA polymerase gamma-2, accessory subunit (Polg2) resulting in a nonsense mutation, Tyr265Stop (Y265X), which co-segregated with RCALC2. Kidneys of mutant mice (Polg2(+/Y265X) ) had lower POLG2 mRNA and protein expression, compared to wild-type littermates (Polg2(+/+) ). The Polg2(+/Y265X) and Polg2(+/+) mice had similar plasma concentrations of sodium, potassium, calcium, phosphate, chloride, urea, creatinine, glucose and alkaline phosphatase activity; and similar urinary fractional excretion of calcium, phosphate, oxalate and protein. Polg2 encodes the minor subunit of the mitochondrial DNA (mtDNA) polymerase and the mtDNA content in Polg2(+/Y265X) kidneys was reduced compared to Polg2(+/+) mice, and cDNA expression profiling revealed differential expression of 26 genes involved in several biological processes including mitochondrial DNA function, apoptosis and ubiquitination, the complement pathway, and inflammatory pathways. In addition, plasma of Polg2(+/Y265X) mice, compared to Polg2(+/+) littermates had higher levels of reactive oxygen species. Thus, our studies have identified a mutant mouse model for inherited renal calcification associated with a Polg2 nonsense mutation.
Keywords:Aging, Genetic Animal Models, Animal Models, Other, Cell/Tissue Signaling, Endocrine Pathways, Disorders of Calcium/Phosphate Metabolism, Animals, Mice
Source:Journal of Bone and Mineral Research
ISSN:0884-0431
Publisher:Wiley
Volume:34
Number:3
Page Range:497-507
Date:March 2019
Official Publication:https://doi.org/10.1002/jbmr.3624
PubMed:View item in PubMed

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