ArticleBMC medicine2022
Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes.
Article in BMC medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 22 citations in OpenAlex.
- Centriolar Protein POC5 Regulates Human Adipogenesis and Cellular Senescence: Insights From a Novel Metabolic Ciliopathy.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Association of a Homozygous TYMP c.131G>C Variant With MNGIE in a Chinese Pedigree: Insights From Genetic Analysis and Computational Modeling.Molecular genetics & genomic medicine · 2026Article
- TYMP upregulation mediated by the hyperactivated IL-17/NF-κB1 axis promotes psoriasis through enhancing aberrant keratinization and neutrophil-mediated inflammation.Biology direct · 2026Article
- Expansion of the Phenotypic Spectrum of MNGIE: Lipodystrophy and Metabolic Alterations Associated with a p.Arg393_Val400dup TYMP Variant.International journal of molecular sciences · 2025Article
- Untargeted Plasma Metabolomics Extends the Biomarker Profile of Mitochondrial Neurogastrointestinal Encephalomyopathy.International journal of molecular sciences · 2025Article
- Preclinical evaluation of candidate "kill or cure" strategies to treat MFN2-related lipodystrophy.Molecular medicine (Cambridge, Mass.) · 2025Article
- Gain of Function NOTCH3 Variants Cause Familial Partial Lipodystrophy Due to Activation of Senescence Pathways.Diabetes · 2025Article
- Article
- Identification of galangin as a therapeutic candidate for primary biliary cholangitis via systematic druggable genome-wide Mendelian randomization analysis and experimental validation.Frontiers in pharmacology · 2025Article
- The senescence-associated secretome of Hedgehog-deficient hepatocytes drives MASLD progression.The Journal of clinical investigation · 2024Article
- ADH1B, the adipocyte-enriched alcohol dehydrogenase, plays an essential, cell-autonomous role in human adipogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Lysosomal dysfunction and overload of nucleosides in thymidine phosphorylase deficiency of MNGIE.Journal of translational medicine · 2024Article
- Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling.Nature genetics · 2023Article
- The necroptosis-inducing pseudokinase mixed lineage kinase domain-like regulates the adipogenic differentiation of pre-adipocytes.iScience · 2022Article
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18 authors at 11 institutions in 3 countries.
Funding
Abstract
backgroundThymidine 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.
methodsDeep 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.
resultsAll 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.
conclusionsThe 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.
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