Universität zu Köln

Kudin, Alexei P., Baron, Gregor, Zsurka, Gabor ORCID: 0000-0002-6379-849X, Hampel, Kevin G., Elger, Christian E., Grote, Alexander, Weber, Yvonne, Lerche, Holger, Thiele, Holger, Nuernberg, Peter, Schulz, Herbert, Ruppert, Ann-Kathrin, Sander, Thomas, Cheng, Qing, Arner, Elias S. J., Schomburg, Lutz, Seeher, Sandra, Fradejas-Villar, Noelia, Schweizer, Ulrich ORCID: 0000-0003-1380-4780 and Kunz, Wolfram S. ORCID: 0000-0003-1113-3493 (2017). Homozygous mutation in TXNRD1 is associated with genetic generalized epilepsy. Free Radic. Biol. Med., 106. S. 270 - 278. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1873-4596

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kudin, Alexei P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Baron, Gregor UNSPECIFIED UNSPECIFIED UNSPECIFIED Zsurka, Gabor UNSPECIFIED orcid.org/0000-0002-6379-849X UNSPECIFIED Hampel, Kevin G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Elger, Christian E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Grote, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Yvonne UNSPECIFIED UNSPECIFIED UNSPECIFIED Lerche, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Schulz, Herbert UNSPECIFIED UNSPECIFIED UNSPECIFIED Ruppert, Ann-Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Sander, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Cheng, Qing UNSPECIFIED UNSPECIFIED UNSPECIFIED Arner, Elias S. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schomburg, Lutz UNSPECIFIED UNSPECIFIED UNSPECIFIED Seeher, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Fradejas-Villar, Noelia UNSPECIFIED UNSPECIFIED UNSPECIFIED Schweizer, Ulrich UNSPECIFIED orcid.org/0000-0003-1380-4780 UNSPECIFIED Kunz, Wolfram S. UNSPECIFIED orcid.org/0000-0003-1113-3493 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-232366
DOI:	10.1016/j.freeradbiomed.2017.02.040
Journal or Publication Title:	Free Radic. Biol. Med.
Volume:	106
Page Range:	S. 270 - 278
Date:	2017
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1873-4596
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EARLY EMBRYONIC LETHALITY; THIOREDOXIN REDUCTASE; SELENOPROTEIN BIOSYNTHESIS; MITOCHONDRIAL DYSFUNCTION; DEFICIENCY; PENETRANCE; DISRUPTION; EXPRESSION; SURVIVAL; SEIZURES Multiple languages Biochemistry & Molecular Biology; Endocrinology & Metabolism Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23236