Homozygous mutation in TXNRD1 is associated with genetic generalized epilepsy
| العنوان: | Homozygous mutation in TXNRD1 is associated with genetic generalized epilepsy |
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| المؤلفون: | Noelia Fradejas-Villar, Ann-Kathrin Ruppert, Yvonne G. Weber, Alexander Grote, Herbert Schulz, Christian E. Elger, Gregor Baron, Ulrich Schweizer, Elias S.J. Arnér, Gábor Zsurka, Sandra Seeher, Kevin G. Hampel, Lutz Schomburg, Peter Nürnberg, Alexei P. Kudin, Holger Lerche, Wolfram S. Kunz, Qing Cheng, Holger Thiele, Thomas Sander |
| المصدر: | FREE RADICAL BIOLOGY AND MEDICINE r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe instname |
| بيانات النشر: | Elsevier BV, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Adult, Male, 0301 basic medicine, Thioredoxin Reductase 1, Adolescent, Mutant, Biology, medicine.disease_cause, Biochemistry, law.invention, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Western blot, law, Generalized seizures, TXNRD1, Physiology (medical), Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Child, Muscle, Skeletal, Sanger sequencing, chemistry.chemical_classification, Mutation, Epilepsy, medicine.diagnostic_test, Homozygote, Glutathione, Molecular biology, Blot, Oxidative Stress, 030104 developmental biology, Enzyme, chemistry, Oxidative stress, Child, Preschool, Recombinant DNA, symbols, Epilepsy, Generalized, Female, Reactive Oxygen Species, 030217 neurology & neurosurgery |
| الوصف: | Increased oxidative stress has been widely implicated in the pathogenesis in various forms of human epilepsy. Here, we report a homozygous mutation in TXNRD1 (thioredoxin reductase 1) in a family with genetic generalized epilepsy. TXNRD1 is an essential selenium-containing enzyme involved in detoxification of reactive oxygen species (ROS) and redox signaling. The TXNRD1 mutation p.Pro190Leu affecting a highly conserved amino acid residue was identified by whole-exome sequencing of blood DNA from the index patient. The detected mutation and its segregation within the family- all siblings of the index patient were homozygous and the parents heterozygous-were confirmed by Sanger sequencing. TXNRD1 activity was determined in subcellular fractions from a skeletal muscle biopsy and skin fibroblasts of the index patient and the expression levels of the mutated protein were assessed by Se-75 labeling and Western blot analysis. As result of the mutation, the activity of TXNRD1 was reduced in the patient's fibroblasts and skeletal muscle (to 34 +/- 3% and 16 +/- 8% of controls, respectively). In fibroblasts, we detected reduced Se-75-labeling of the enzyme (41 +/- 3% of controls). An in-depth in vitro kinetic analysis of the recombinant mutated TXNRD1 indicated 30-40% lowered k(cat)/Se values. Therefore, a reduced activity of the enzyme in the patient's tissue samples is explained by (i) lower enzyme turnover and (ii) reduced abundance of the mutated enzyme as confirmed by Western blotting and Se-75 labeling. The mutant fibroblasts were also found to be less resistant to a hydrogen peroxide challenge. Our data agree with a potential role of insufficient ROS detoxification for disease manifestation in genetic generalized epilepsy. |
| تدمد: | 0891-5849 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::369f6a618380fb2d37f75f9727843d91Test https://doi.org/10.1016/j.freeradbiomed.2017.02.040Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....369f6a618380fb2d37f75f9727843d91 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 08915849 |
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