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Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder
I Nishino1, A Spinazzola, M Hirano
1Columbia University College of Physicians and Surgeons, Department of Neurology, 630 West 168 Street, P & S 4-443, New York, NY 10032, USA.
Abstract:
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive human disease associated with multiple deletions of skeletal muscle mitochondrial DNA (mtDNA), which have been ascribed to a defect in communication between the nuclear and mitochondrial genomes. Examination of 12 MNGIE probands revealed homozygous or compound-heterozygous mutations in the gene specifying thymidine phosphorylase (TP), located on chromosome 22q13.32-qter. TP activity in leukocytes from MNGIE patients was less than 5 percent of controls, indicating that loss-of-function mutations in TP cause the disease. The pathogenic mechanism may be related to aberrant thymidine metabolism, leading to impaired replication or maintenance of mtDNA, or both.
Insights
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by thymidine phosphorylase (TP) gene mutations, leading to mitochondrial DNA deletions. This research identifies loss-of-function TP mutations as the cause of MNGIE.
Area of Science:
- Genetics
- Molecular Biology
- Neuroscience
Background:
- Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare, autosomal recessive disorder.
- It is characterized by multiple deletions in skeletal muscle mitochondrial DNA (mtDNA).
- The underlying cause was previously thought to be a defect in nuclear-mitochondrial genome communication.
Purpose of the Study:
- To investigate the genetic basis of MNGIE.
- To identify the specific gene mutations responsible for the disease.
- To elucidate the pathogenic mechanism linking nuclear gene defects to mtDNA instability.
Main Methods:
- Genetic analysis of 12 MNGIE probands.
- Mutation screening of the thymidine phosphorylase (TP) gene.
- Assay of TP enzyme activity in patient leukocytes.
Main Results:
- Identified homozygous or compound-heterozygous mutations in the thymidine phosphorylase (TP) gene in all MNGIE patients.
- TP gene mutations were located on chromosome 22q13.32-qter.
- Leukocyte TP activity in MNGIE patients was significantly reduced (less than 5% of controls).
Conclusions:
- Loss-of-function mutations in the thymidine phosphorylase (TP) gene cause MNGIE.
- The disease mechanism likely involves impaired thymidine metabolism, affecting mtDNA replication or maintenance.
- This finding establishes a direct link between nuclear gene defects and mitochondrial DNA integrity in MNGIE.