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Sibbing, D.* ; Pfeufer, A. ; Perisic, T. ; Mannes, A.M. ; Fritz-Wolf, K.* ; Unwin, S.* ; Sinner, M.F.* ; Gieger, C. ; Gloeckner, C.J. ; Wichmann, H.-E. ; Kremmer, E. ; Schäfer, Z. ; Walch, A.K. ; Hinterseer, M.* ; Näbauer, M.* ; Kääb, S.* ; Kastrati, A.* ; Schömig, A.* ; Meitinger, T. ; Bornkamm, G.W. ; Conrad, M. ; von Beckerath, N.*

Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy.

Eur. Heart J. 32, 1121-1133 (2011)
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Aims Cardiac energy requirement is met to a large extent by oxidative phosphorylation in mitochondria that are highly abundant in cardiac myocytes. Human mitochondrial thioredoxin reductase (TXNRD2) is a selenocysteine-containing enzyme essential for mitochondrial oxygen radical scavenging. Cardiac-specific deletion of Txnrd2 in mice results in dilated cardiomyopathy (DCM). The aim of this study was to investigate whether TXNRD2 mutations explain a fraction of monogenic DCM cases. Methods and results Sequencing and subsequent genotyping of TXNRD2 in patients diagnosed with DCM (n = 227) and in DCM-free (n = 683) individuals from the general population sample KORA S4 was performed. The functional impact of observed mutations on Txnrd2 function was tested in mouse fibroblasts. We identified two novel amino acid residue-altering TXNRD2 mutations [175G > A (Ala59Thr) and 1124G > A (Gly375Arg)] in three heterozygous carriers among 227 patients that were not observed in the 683 DCM-free individuals. Both DCM-associated mutations result in amino acid substitutions of highly conserved residues in helices contributing to the flavin-adenine dinucleotide (FAD)-binding domain of TXNRD2. Functional analysis of both mutations in Txnrd2(-/-) mouse fibroblasts revealed that contrasting to wild-type (wt) Txnrd2, neither mutant did restore Txnrd2 function. Mutants even impaired the survival of Txnrd2 wt cells under oxidative stress by a dominant-negative mechanism. Conclusion For the first time, we describe mutations in DCM patients in a gene involved in the regulation of cellular redox state. TXNRD2 mutations may explain a fraction of human DCM disease burden.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Dilated cardiomyopathy; Genetics; TXNRD2
ISSN (print) / ISBN 0195-668X
e-ISSN 1522-9645
Quellenangaben Band: 32, Heft: 9, Seiten: 1121-1133 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Begutachtungsstatus Peer reviewed