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Endocrine Abstracts (2014) 34 OC4.6 | DOI: 10.1530/endoabs.34.OC4.6

1Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK; 2Mary Lyon Centre, Medical Research Council, Harwell, UK; 3The University of Queensland Diamantina Institute, Translational Research Institute, Wooloongabba, Queensland, Australia; 4Mammalian Genetics Unit, Medical Research Council, Harwell, UK.


Renal calcification (nephrocalcinosis), which has a multi-factorial etiology involving environmental and genetic determinants, affects ~8% of adults by 70 years. Nephrocalcinosis may occur as a familial disorder in ~65% of patients, and in 70% of patients, nephrocalcinosis may be associated with endocrine and metabolic disorders that include primary hyperparathyroidism, renal tubular acidosis, hypercalciuria, cystinuria, and hyperoxaluria. Investigations of families with hereditary nephrocalcinosis have identified the involvement of genes encoding the chloride/proton antiporter CLC-5, and claudin-16, but further progress has been limited as large families are not available for genetic linkage and mapping studies. To overcome this limitation, we embarked on establishing mouse models for nephrocalcinosis by performing abdominal X-rays to identify renal opacities in 1745 12-month-old male mice derived by N-ethyl-N-nitrosourea (ENU) mutagenesis. This identified a mouse with renal calcification, designated RCALC2, that was inherited as an autosomal dominant trait. Genome-wide mapping located the Rcalc2 locus to a ~16 Mbp region on chromosome 11D-E2 and whole-exome sequence analysis revealed a heterozygous c.C795A substitution in polymerase gamma-2, accessory subunit, Polg2, that resulted in a nonsense mutation (Tyr265Stop). Further analysis of Polg2, which encodes the minor subunit of the mitochondrial DNA polymerase and is required for strengthening polymerase–mitochondrial DNA interactions, revealed RCALC2 mouse kidneys to have lower POLG2 mRNA and protein expression, and co-immunoprecipitation studies showed the mutant to have a loss of interaction with the major polymerase subunit, POLG. This was not associated with a change in mitochondrial DNA content in RCALC2 kidneys, or mitochondrial function such as reactive oxygen species (ROS) generation or apoptosis, which was assessed by Oxiselect Intracellular ROS and Caspase-Glo-3/7 luminescent assays, respectively. In conclusion, RCALC2 is a novel mouse model of renal calcification that may reveal new functions for POLG2 in endocrine and metabolic diseases associated with nephrocalcinosis.

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