Universität zu Köln

Gorvin, Caroline M., Ahmad, Bushra N., Stechman, Michael J., Loh, Nellie Y., Hough, Tertius A., Leo, Paul, Marshall, Mhairi, Sethi, Siddharth, Bentley, Liz, Piret, Sian E., Reed, Anita, Jeyabalan, Jeshmi, Christie, Paul T., Wells, Sara, Simon, Michelle M., Mallon, Ann-Marie, Schulz, Herbert, Huebner, Norbert, Brown, Matthew A., Cox, Roger D., Brown, Steve D. and Thakker, Rajesh V. (2019). 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. J. Bone Miner. Res., 34 (3). S. 497 - 508. HOBOKEN: WILEY. ISSN 1523-4681

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Abstract

Renal calcification (RCALC) resulting in nephrolithiasis and nephrocalcinosis, which affects similar to 10% of adults by 70 years of age, involves environmental and genetic etiologies. Thus, nephrolithiasis and nephrocalcinosis occurs as an inherited disorder in similar to 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). Genomewide mapping located the Rcalc2 locus to a similar to 16-Mbp 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. (c) 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gorvin, Caroline M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ahmad, Bushra N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stechman, Michael J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Loh, Nellie Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hough, Tertius A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Leo, Paul UNSPECIFIED UNSPECIFIED UNSPECIFIED Marshall, Mhairi UNSPECIFIED UNSPECIFIED UNSPECIFIED Sethi, Siddharth UNSPECIFIED UNSPECIFIED UNSPECIFIED Bentley, Liz UNSPECIFIED UNSPECIFIED UNSPECIFIED Piret, Sian E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reed, Anita UNSPECIFIED UNSPECIFIED UNSPECIFIED Jeyabalan, Jeshmi UNSPECIFIED UNSPECIFIED UNSPECIFIED Christie, Paul T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wells, Sara UNSPECIFIED UNSPECIFIED UNSPECIFIED Simon, Michelle M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mallon, Ann-Marie UNSPECIFIED UNSPECIFIED UNSPECIFIED Schulz, Herbert UNSPECIFIED UNSPECIFIED UNSPECIFIED Huebner, Norbert UNSPECIFIED UNSPECIFIED UNSPECIFIED Brown, Matthew A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cox, Roger D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brown, Steve D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Thakker, Rajesh V. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-155313
DOI:	10.1002/jbmr.3624
Journal or Publication Title:	J. Bone Miner. Res.
Volume:	34
Number:	3
Page Range:	S. 497 - 508
Date:	2019
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1523-4681
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MOLECULAR-MECHANISMS; STONE FORMATION; KIDNEY; NEPHROLITHIASIS; VARIANTS; INSIGHTS; MODEL; NEPHROCALCINOSIS; PREVALENCE; DISORDERS Multiple languages Endocrinology & Metabolism Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15531