دورية أكاديمية
أعرض في EDS

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.

التفاصيل البيبلوغرافية
العنوان: 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.
المؤلفون: Gorvin CM; Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., Ahmad BN; Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., Stechman MJ; Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., Loh NY; Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., Hough TA; Mary Lyon Centre and Mammalian Genetics Unit, Medical Research Council, Harwell, UK., Leo P; Translational Genomics Group, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology at Translational Research Institute, Brisbane, Australia., Marshall M; Translational Genomics Group, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology at Translational Research Institute, Brisbane, Australia., Sethi S; Mary Lyon Centre and Mammalian Genetics Unit, Medical Research Council, Harwell, UK., Bentley L; Mary Lyon Centre and Mammalian Genetics Unit, Medical Research Council, Harwell, UK., Piret SE; Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., Reed A; Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., Jeyabalan J; Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., Christie PT; Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., Wells S; Mary Lyon Centre and Mammalian Genetics Unit, Medical Research Council, Harwell, UK., Simon MM; Mary Lyon Centre and Mammalian Genetics Unit, Medical Research Council, Harwell, UK., Mallon AM; Mary Lyon Centre and Mammalian Genetics Unit, Medical Research Council, Harwell, UK., Schulz H; Max-Delbrück-Center for Molecular Medicine, Berlin, Germany., Huebner N; Max-Delbrück-Center for Molecular Medicine, Berlin, Germany., Brown MA; Translational Genomics Group, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology at Translational Research Institute, Brisbane, Australia., Cox RD; Mary Lyon Centre and Mammalian Genetics Unit, Medical Research Council, Harwell, UK., Brown SD; Mary Lyon Centre and Mammalian Genetics Unit, Medical Research Council, Harwell, UK., Thakker RV; Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
المصدر: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2019 Mar; Vol. 34 (3), pp. 497-507. Date of Electronic Publication: 2018 Dec 14.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: United States NLM ID: 8610640 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1523-4681 (Electronic) Linking ISSN: 08840431 NLM ISO Abbreviation: J Bone Miner Res Subsets: MEDLINE
أسماء مطبوعة: Publication: January 2024- : [Oxford] : Oxford University Press
Original Publication: New York : Mary Ann Liebert, Inc., c1986-
مواضيع طبية MeSH: Calcinosis*/genetics , Calcinosis*/metabolism , Calcinosis*/pathology , Codon, Terminator* , DNA Polymerase gamma*/genetics , DNA Polymerase gamma*/metabolism , Kidney*/metabolism , Kidney*/pathology , Kidney Diseases*/genetics , Kidney Diseases*/metabolism , Kidney Diseases*/pathology, Ethylnitrosourea/*toxicity, Animals ; Mice ; Mice, Mutant Strains
مستخلص: Renal calcification (RCALC) resulting in nephrolithiasis and nephrocalcinosis, which affects ∼10% of adults by 70 years of age, involves environmental and genetic etiologies. Thus, nephrolithiasis and nephrocalcinosis occurs as an inherited disorder in ∼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 ∼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. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
(© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.)
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معلومات مُعتمدة: MC_UP_1502/1 United Kingdom MRC_ Medical Research Council; G1000467 United Kingdom MRC_ Medical Research Council; G0600702 United Kingdom MRC_ Medical Research Council; MC_U142684171 United Kingdom MRC_ Medical Research Council; G9825289 United Kingdom MRC_ Medical Research Council; United Kingdom Wellcome Trust; MC_U142661184 United Kingdom MRC_ Medical Research Council
فهرسة مساهمة: Keywords: AGING; ANIMAL MODELS; CELL/TISSUE SIGNALING; DISORDERS OF CALCIUM/PHOSPHATE METABOLISM; ENDOCRINE PATHWAYS; GENETIC ANIMAL MODELS; OTHER
المشرفين على المادة: 0 (Codon, Terminator)
EC 2.7.7.7 (DNA Polymerase gamma)
EC 2.7.7.7 (Polg protein, mouse)
P8M1T4190R (Ethylnitrosourea)
تواريخ الأحداث: Date Created: 20181106 Date Completed: 20200622 Latest Revision: 20220129
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC6446808
DOI: 10.1002/jbmr.3624
PMID: 30395686
قاعدة البيانات: MEDLINE
الوصف
تدمد:1523-4681
DOI:10.1002/jbmr.3624