TYMP – Mitochondrial Disease

TYMP encodes thymidine phosphorylase, a cytosolic enzyme critical for pyrimidine salvage and mitochondrial DNA maintenance. Autosomal recessive loss-of-function variants in TYMP cause a spectrum of mitochondrial diseases, most notably Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE), and broader mitochondrial disorders characterized by mtDNA depletion, progressive gastrointestinal dysmotility, leukoencephalopathy, and optic atrophy (PMID:29485812).

Genetic evidence supports a strong association between TYMP and mitochondrial disease. At least six unrelated probands from four consanguineous or multiplex families harbor bi-allelic TYMP variants including compound heterozygous CNV with c.261G>T (p.Glu87Asp) (PMID:23838601), homozygous c.3371A>C (p.?) (PMID:29485812), and homozygous c.1205T>A (p.Leu402Gln) (PMID:35841120). These cases display consistent autosomal recessive segregation.

Segregation analyses in multiple pedigrees reveal that parents and unaffected siblings carry single heterozygous TYMP variants without clinical symptoms, confirming recessive inheritance, although no additional affected relatives beyond probands were reported.

Functional assays demonstrate absent thymidine phosphorylase activity in muscle homogenates and blood of affected individuals (PMID:29485812). Patient cells exhibit mtDNA copy‐number depletion without large deletions (PMID:35841120).

Further experimental data from metabolomics studies reveal marked alterations in nucleoside, bile acid, and lipid metabolism in TYMP-deficient fibroblasts that are rescued by TP overexpression (PMID:37603049). Multiscale molecular dynamics simulations corroborate that MNGIE-associated variants (e.g., R44Q, G145R, E289A) destabilize TP structure and impair thymidine binding (PMID:40111159).

Collectively, these findings establish TYMP haploinsufficiency as a definitive mechanism underlying autosomal recessive mitochondrial disease. The combination of robust genetic segregation, enzyme deficiency assays, mtDNA depletion, metabolomic profiling, and computational modeling underpins a Strong ClinGen classification.

Key Take-home: TYMP should be included in gene panels for autosomal recessive mitochondrial disorders, as bi-allelic variants reliably predict clinical MNGIE and related mitochondrial disease phenotypes.

References

• Genetic counseling (Geneva, Switzerland) • 2016 • Mitochondrial Neurogastrointestinal Encephalopathy: Clinical, Biochemical and Molecular Study in Three Egyptian Patients. PMID:29485812
• International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience • 2022 • A novel thymidine phosphorylase mutation in a family with Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE): Molecular docking, dynamic simulation and computational investigations. PMID:35841120
• Journal of molecular medicine (Berlin, Germany) • 2023 • Distinctive metabolic remodeling in TYMP deficiency beyond mitochondrial dysfunction. PMID:37603049
• Bioinformation • 2024 • Insights from the SNP analysis of TYMP gene linking MNGIE. PMID:38712004
• The journal of physical chemistry. B • 2025 • Multiscale Simulations and Profiling of Human Thymidine Phosphorylase Mutations: Insights into Structural, Dynamics, and Functional Impacts in Mitochondrial Neurogastrointestinal Encephalopathy. PMID:40111159

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