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García-Flores LA, Green CL, Mitchell SE, Promislow DEL, Lusseau D, Douglas A, Speakman JR. The effects of graded calorie restriction XVII: Multitissue metabolomics reveals synthesis of carnitine and NAD, and tRNA charging as key pathways. Proc Natl Acad Sci U S A 2021; 118:e2101977118. [PMID: 34330829 PMCID: PMC8346868 DOI: 10.1073/pnas.2101977118] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The evolutionary context of why caloric restriction (CR) activates physiological mechanisms that slow the process of aging remains unclear. The main goal of this analysis was to identify, using metabolomics, the common pathways that are modulated across multiple tissues (brown adipose tissue, liver, plasma, and brain) to evaluate two alternative evolutionary models: the "disposable soma" and "clean cupboards" ideas. Across the four tissues, we identified more than 10,000 different metabolic features. CR altered the metabolome in a graded fashion. More restriction led to more changes. Most changes, however, were tissue specific, and in some cases, metabolites changed in opposite directions in different tissues. Only 38 common metabolic features responded to restriction in the same way across all four tissues. Fifty percent of the common altered metabolites were carboxylic acids and derivatives, as well as lipids and lipid-like molecules. The top five modulated canonical pathways were l-carnitine biosynthesis, NAD (nicotinamide adenine dinucleotide) biosynthesis from 2-amino-3-carboxymuconate semialdehyde, S-methyl-5'-thioadenosine degradation II, NAD biosynthesis II (from tryptophan), and transfer RNA (tRNA) charging. Although some pathways were modulated in common across tissues, none of these reflected somatic protection, and each tissue invoked its own idiosyncratic modulation of pathways to cope with the reduction in incoming energy. Consequently, this study provides greater support for the clean cupboards hypothesis than the disposable soma interpretation.
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Affiliation(s)
- Libia Alejandra García-Flores
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Chaoyang, Beijing 100101, China
| | - Cara L Green
- Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen AB39 2PN, Scotland, United Kingdom
| | - Sharon E Mitchell
- Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen AB39 2PN, Scotland, United Kingdom
| | - Daniel E L Promislow
- Department of Lab Medicine and Pathology, University of Washington, Seattle, WA 98195
- Department of Biology, University of Washington, Seattle, WA 98195
| | - David Lusseau
- Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen AB39 2PN, Scotland, United Kingdom
| | - Alex Douglas
- Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen AB39 2PN, Scotland, United Kingdom
| | - John R Speakman
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Chaoyang, Beijing 100101, China;
- Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen AB39 2PN, Scotland, United Kingdom
- Center for Energy Metabolism and Reproduction, Shenzhen Institutes of Advanced Technology, Shenzhen 518055, China
- Center of Excellence for Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China
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Sharma M, Gowrishankar S, Jeloka TK. A Rare Case of APRT Deficiency with End-stage Renal Failure and Successful Renal Transplant. Indian J Nephrol 2021; 31:57-60. [PMID: 33994690 PMCID: PMC8101663 DOI: 10.4103/ijn.ijn_202_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Revised: 09/05/2019] [Accepted: 10/30/2019] [Indexed: 11/30/2022] Open
Abstract
Renal calculus disease is a common cause of renal injury. However, crystal nephropathy (uric acid, oxalate, and dihydroxyadenine) can present as chronic kidney disease without any evidence of renal stones. If left undiagnosed, there is a potential chance of recurrence in the allograft leading to graft failure after transplantation. Pretransplant identification and management can avoid such complications. Here, we describe a case of APRT deficiency leading to crystal nephropathy and end-stage renal failure in a patient who underwent a successful kidney transplant.
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Affiliation(s)
- Manish Sharma
- Department of Nephrology, Aditya Birla Memorial Hospital, Pune, Maharashtra, India
| | | | - Tarun K Jeloka
- Department of Nephrology, Aditya Birla Memorial Hospital, Pune, Maharashtra, India
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Wintergerst L, Selmansberger M, Maihoefer C, Schüttrumpf L, Walch A, Wilke C, Pitea A, Woischke C, Baumeister P, Kirchner T, Belka C, Ganswindt U, Zitzelsberger H, Unger K, Hess J. A prognostic mRNA expression signature of four 16q24.3 genes in radio(chemo)therapy-treated head and neck squamous cell carcinoma (HNSCC). Mol Oncol 2018; 12:2085-2101. [PMID: 30259648 PMCID: PMC6275282 DOI: 10.1002/1878-0261.12388] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 08/13/2018] [Accepted: 09/12/2018] [Indexed: 01/28/2023] Open
Abstract
Previously, we have shown that copy number gain of the chromosomal band 16q24.3 is associated with impaired clinical outcome of radiotherapy‐treated head and neck squamous cell carcinoma (HNSCC) patients. We set out to identify a prognostic mRNA signature from genes located on 16q24.3 in radio(chemo)therapy‐treated HNSCC patients of the TCGA (The Cancer Genome Atlas, n = 99) cohort. We applied stepwise forward selection using expression data of 41 16q24.3 genes. The resulting optimal Cox‐proportional hazards regression model included the genes APRT, CENPBD1, CHMP1A, and GALNS. Afterward, the prognostic value of the classifier was confirmed in an independent cohort of HNSCC patients treated by adjuvant radio(chemo)therapy (LMU‐KKG cohort). The signature significantly differentiated high‐ and low‐risk patients with regard to overall survival (HR = 2.01, 95% CI 1.10–3.70; P = 0.02125), recurrence‐free survival (HR = 1.84, 95% CI 1.01–3.34; P = 0.04206), and locoregional recurrence‐free survival (HR = 1.87, 95% CI 1.03–3.40; P = 0.03641). The functional impact of the four signature genes was investigated after reconstruction of a gene association network from transcriptome data of the TCGA HNSCC cohort using a partial correlation approach. Subsequent pathway enrichment analysis of the network neighborhood (first and second) of the signature genes suggests involvement of HNSCC‐associated signaling pathways such as apoptosis, cell cycle, cell adhesion, EGFR, JAK‐STAT, and mTOR. Furthermore, a detailed analysis of the first neighborhood revealed a cluster of co‐expressed genes located on chromosome 16q, substantiating the impact of 16q24.3 alterations in poor clinical outcome of HNSCC. The reported gene expression signature represents a prognostic marker in HNSCC patients following postoperative radio(chemo)therapy.
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Affiliation(s)
- Ludmila Wintergerst
- Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.,Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany
| | - Martin Selmansberger
- Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany
| | - Cornelius Maihoefer
- Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.,Department of Radiation Oncology, University Hospital, LMU Munich, Germany
| | - Lars Schüttrumpf
- Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.,Department of Radiation Oncology, University Hospital, LMU Munich, Germany
| | - Axel Walch
- Research Unit Analytical Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany
| | - Christina Wilke
- Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany
| | - Adriana Pitea
- Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.,Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany
| | | | - Philipp Baumeister
- Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.,Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, LMU Munich, Germany
| | - Thomas Kirchner
- Institute of Pathology, Faculty of Medicine, LMU Munich, Germany
| | - Claus Belka
- Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.,Department of Radiation Oncology, University Hospital, LMU Munich, Germany.,German Cancer Consortium (DKTK), Munich, Germany
| | - Ute Ganswindt
- Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.,Department of Radiation Oncology, University Hospital, LMU Munich, Germany.,Department of Therapeutic Radiology and Oncology, Innsbruck Medical University, Austria
| | - Horst Zitzelsberger
- Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.,Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.,Department of Radiation Oncology, University Hospital, LMU Munich, Germany
| | - Kristian Unger
- Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.,Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.,Department of Radiation Oncology, University Hospital, LMU Munich, Germany
| | - Julia Hess
- Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.,Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.,Department of Radiation Oncology, University Hospital, LMU Munich, Germany
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Ceballos-Picot I, Daudon M, Harambat J, Bensman A, Knebelmann B, Bollée G. 2,8-Dihydroxyadenine urolithiasis: a not so rare inborn error of purine metabolism. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2015; 33:241-52. [PMID: 24940675 DOI: 10.1080/15257770.2013.853780] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Adenine phosphoribosyltransferase (APRT) deficiency is a rare inherited metabolic disorder that leads to the formation and hyperexcretion of 2,8-dihydroxyadenine (DHA) into urine. The low solubility of DHA results in precipitation and formation of urinary crystals and kidney stones. The disease can be present as recurrent urolithiasis or nephropathy secondary to crystal precipitation into renal parenchyma (DHA nephropathy). The diagnostic tools available, including stone analysis, crystalluria, and APRT activity in red blood cells, make the diagnosis easy to confirm when APRT deficiency is suspected. However, the lack of recognition of this metabolic disorder frequently resulted in a delay in diagnosis and treatment with grave consequences. The early recognition and treatment of APRT deficiency are of crucial importance to prevent irreversible loss of renal function. This review summarizes the genetic and metabolic mechanisms underlying DHA stones formation and chronic kidney disease, along with the issues of diagnosis and management of APRT deficiency. Moreover, we report the mutations in the APRT gene responsible for APRT deficiency in 51 French patients (43 families) including 22 pediatric cases (18 families) among the 64 patients identified in the biochemistry laboratories of Necker Hospital, Paris (1978-2013).
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Affiliation(s)
- Irène Ceballos-Picot
- a Université Paris Descartes, Assistance Publique Hôpitaux de Paris, Laboratoire de Biochimie Métabolomique et protéomique, Hôpital Necker-Enfants Malades , Paris , France
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Bollée G, Harambat J, Bensman A, Knebelmann B, Daudon M, Ceballos-Picot I. Adenine phosphoribosyltransferase deficiency. Clin J Am Soc Nephrol 2012; 7:1521-7. [PMID: 22700886 DOI: 10.2215/cjn.02320312] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Complete adenine phosphoribosyltransferase (APRT) deficiency is a rare inherited metabolic disorder that leads to the formation and hyperexcretion of 2,8-dihydroxyadenine (DHA) into urine. The low solubility of DHA results in precipitation of this compound and the formation of urinary crystals and stones. The disease can present as recurrent urolithiasis or nephropathy secondary to crystal precipitation into renal parenchyma (DHA nephropathy). The diagnostic tools available-including stone analysis, crystalluria, and APRT activity measurement-make the diagnosis easy to confirm when APRT deficiency is suspected. However, the disease can present at any age, and the variability of symptoms can present a diagnostic challenge to many physicians. The early recognition and treatment of APRT deficiency are of crucial importance for preventing irreversible loss of renal function, which still occurs in a non-negligible proportion of cases. This review summarizes the genetic and metabolic mechanisms underlying stone formation and renal disease, along with the diagnosis and management of APRT deficiency.
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Affiliation(s)
- Guillaume Bollée
- Association pour l'Utilisation du Rein Artificiel and Inserm U970, Paris, France.
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Broderick TP, Schaff DA, Bertino AM, Dush MK, Tischfield JA, Stambrook PJ. Comparative anatomy of the human APRT gene and enzyme: nucleotide sequence divergence and conservation of a nonrandom CpG dinucleotide arrangement. Proc Natl Acad Sci U S A 1987; 84:3349-53. [PMID: 3554238 PMCID: PMC304867 DOI: 10.1073/pnas.84.10.3349] [Citation(s) in RCA: 74] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
The functional human adenine phosphoribosyltransferase (APRT) gene is less than 2.6 kilobases in length and contains five exons. The amino acid sequences of APRTs have been highly conserved throughout evolution. The human enzyme is 82%, 90%, and 40% identical to the mouse, hamster, and Escherichia coli enzymes, respectively. The promoter region of the human APRT gene, like that of several other "housekeeping" genes, lacks "TATA" and "CCAAT" boxes but contains five GC boxes that are potential binding sites for the Sp1 transcription factor. The distal three, however, are dispensable for gene expression. Comparison between human and mouse APRT gene nucleotide sequences reveals a high degree of homology within protein coding regions but an absence of significant homology in 5' flanking, 3' untranslated, and intron sequences, except for similarly positioned GC boxes in the promoter region and a 26-base-pair region in intron 3. This 26-base-pair sequence is 92% identical with a similarly positioned sequence in the mouse gene and is also found in intron 3 of the hamster gene, suggesting that its retention may be a consequence of stringent selection. The positions of all introns have been precisely retained in the human and both rodent genes, as has an unusual AG/GC donor splice site in intron 2. Particularly striking is the distribution of CpG dinucleotides within human and rodent APRT genes. Although the nucleotide sequences of intron 1 and the 5' flanking regions of human and mouse APRT genes have no substantial homology, they have a frequency of CpG dinucleotides that is much higher than expected and nonrandom considering the G + C content of the gene. Retention of an elevated CpG dinucleotide content, despite loss of sequence homology, suggests that there may be selection for CpG dinucleotides in these regions and that their maintenance may be important for APRT gene function.
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