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Published on: August 24, 2013
Association of a Homozygous TYMP c.131G>C Variant With MNGIE in a Chinese Pedigree: Insights From Genetic Analysis
1Department of Neurology, Affiliated Hospital of Southwest Medical University, Luzhou, China.
Background:
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in TYMP, which disrupt thymidine metabolism. This study aimed to characterize a novel homozygous TYMP variant and provide insights into its potential structural and functional consequences through bioinformatic analyses.
Methods:
We identified a homozygous TYMP variant (c.131G>C, p.R44P) in a proband with MNGIE using whole-exome sequencing and Sanger sequencing. Computational structural analyses and molecular modeling were performed to predict the impact of the R44P substitution on thymidine phosphorylase (TP) stability, homodimerization, catalytic activity, and substrate binding.
Results:
The homozygous TYMP c.131G>C variant was confirmed in the proband. Computational analyses suggested that the p.R44P substitution may destabilize TP and potentially impair homodimerization. Molecular modeling further predicted altered thymidine binding and disrupted active-site geometry. These predicted perturbations are hypothesized to contribute to defective nucleotide metabolism, thymidine accumulation, and deoxynucleotide triphosphate pool imbalance, which may ultimately result in mitochondrial genomic instability manifesting as mitochondrial DNA deletions and depletion.
Conclusion:
Our findings report the TYMP c.131G>C variant in a homozygous configuration, extending beyond a recently described compound heterozygous case. The bioinformatic predictions support the classification of this variant as likely pathogenic in MNGIE, though functional studies are warranted to validate these findings.
Insights
A novel homozygous TYMP variant (c.131G>C, p.R44P) was identified in a patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Bioinformatic analyses suggest this variant likely impairs thymidine phosphorylase function, contributing to MNGIE pathogenesis.
Area of Science:
- Genetics and Molecular Biology
- Biochemistry
- Bioinformatics
Background:
- Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder.
- It stems from mutations in the TYMP gene, affecting thymidine metabolism.
- Understanding novel TYMP variants is crucial for MNGIE diagnosis and treatment.
Purpose of the Study:
- To characterize a newly identified homozygous TYMP variant (c.131G>C, p.R44P) in an MNGIE patient.
- To investigate the potential structural and functional impacts of this variant using computational methods.
- To assess the variant's pathogenicity in the context of MNGIE.
Main Methods:
- Whole-exome and Sanger sequencing to identify the TYMP variant.
- Computational structural analyses to predict effects on thymidine phosphorylase (TP) stability and function.
- Molecular modeling to assess substrate binding and active-site alterations.
Main Results:
- The homozygous TYMP c.131G>C variant was confirmed in the proband.
- Computational predictions indicated the p.R44P substitution may destabilize TP and impair homodimerization.
- Molecular modeling suggested altered thymidine binding and disrupted active-site geometry, potentially leading to MNGIE pathology.
Conclusions:
- The study reports the TYMP c.131G>C variant in a homozygous state, expanding knowledge beyond compound heterozygous cases.
- Bioinformatic predictions support classifying this variant as likely pathogenic for MNGIE.
- Further functional studies are recommended to validate these computational findings.
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