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Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes.

Gautheron, J; Lima, L; Akinci, B; Zammouri, J; Auclair, M; Ucar, SK; Ozen, S; Altay, C; Bax, BE; Nemazanyy, I; et al. Gautheron, J; Lima, L; Akinci, B; Zammouri, J; Auclair, M; Ucar, SK; Ozen, S; Altay, C; Bax, BE; Nemazanyy, I; Lenoir, V; Prip-Buus, C; Acquaviva-Bourdain, C; Lascols, O; Fève, B; Vigouroux, C; Noel, E; Jéru, I (2022) Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes. BMC Med, 20 (1). p. 95. ISSN 1741-7015 https://doi.org/10.1186/s12916-022-02296-2
SGUL Authors: Bax, Bridget Elizabeth

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Abstract

BACKGROUND: Thymidine phosphorylase (TP), encoded by the TYMP gene, is a cytosolic enzyme essential for the nucleotide salvage pathway. TP catalyzes the phosphorylation of the deoxyribonucleosides, thymidine and 2'-deoxyuridine, to thymine and uracil. Biallelic TYMP variants are responsible for Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE), an autosomal recessive disorder characterized in most patients by gastrointestinal and neurological symptoms, ultimately leading to death. Studies on the impact of TYMP variants in cellular systems with relevance to the organs affected in MNGIE are still scarce and the role of TP in adipose tissue remains unexplored. METHODS: Deep phenotyping was performed in three patients from two families carrying homozygous TYMP variants and presenting with lipoatrophic diabetes. The impact of the loss of TP expression was evaluated using a CRISPR-Cas9-mediated TP knockout (KO) strategy in human adipose stem cells (ASC), which can be differentiated into adipocytes in vitro. Protein expression profiles and cellular characteristics were investigated in this KO model. RESULTS: All patients had TYMP loss-of-function variants and first presented with generalized loss of adipose tissue and insulin-resistant diabetes. CRISPR-Cas9-mediated TP KO in ASC abolished adipocyte differentiation and decreased insulin response, consistent with the patients' phenotype. This KO also induced major oxidative stress, altered mitochondrial functions, and promoted cellular senescence. This translational study identifies a new role of TP by demonstrating its key regulatory functions in adipose tissue. CONCLUSIONS: The implication of TP variants in atypical forms of monogenic diabetes shows that genetic diagnosis of lipodystrophic syndromes should include TYMP analysis. The fact that TP is crucial for adipocyte differentiation and function through the control of mitochondrial homeostasis highlights the importance of mitochondria in adipose tissue biology.

Item Type: Article
Additional Information: © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Keywords: Adipose stem cell, CRISPR-Cas9, Diabetes, Genetics, Insulin resistance, Lipodystrophy, Mitochondria, Mutation, Oxidative stress, TP, Thymidine phosphorylase, Adipocytes, Diabetes Mellitus, Lipoatrophic, Humans, Insulins, Mutation, Thymidine Phosphorylase, Adipocytes, Humans, Diabetes Mellitus, Lipoatrophic, Thymidine Phosphorylase, Mutation, Insulins, TP, Thymidine phosphorylase, Lipodystrophy, Insulin resistance, Mutation, Adipose stem cell, CRISPR-Cas9, Mitochondria, Oxidative stress, Diabetes, Genetics, General & Internal Medicine, 11 Medical and Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: BMC Med
ISSN: 1741-7015
Language: eng
Dates:
DateEvent
28 March 2022Published
10 February 2022Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
R18139DDMairie de ParisUNSPECIFIED
R19114DDSociété Francophone du DiabèteUNSPECIFIED
ARF20170938613Fondation pour la Recherche MédicaleUNSPECIFIED
EQU202003010517Fondation pour la Recherche MédicaleUNSPECIFIED
ANR-21-CE17-0002-01Agence Nationale de la Recherchehttp://dx.doi.org/10.13039/501100001665
EQU201903007868Fondation pour la Recherche MédicaleUNSPECIFIED
PubMed ID: 35341481
Web of Science ID: WOS:000773402400001
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/114303
Publisher's version: https://doi.org/10.1186/s12916-022-02296-2

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