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


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.


CONCLUSIONS
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.
Deutsches Herzzentrum München, Munich, Germany.
Dirk
D
Sibbing
Arne
A
Pfeufer
Tamara
T
Perisic
Alexander M
AM
Mannes
Karin
K
Fritz-Wolf
Sarah
S
Unwin
Moritz F
MF
Sinner
Christian
C
Gieger
Christian Johannes
CJ
Gloeckner
Heinz-Erich
HE
Wichmann
Elisabeth
E
Kremmer
Zasie
Z
Schäfer
Axel
A
Walch
Martin
M
Hinterseer
Michael
M
Näbauer
Stefan
S
Kääb
Adnan
A
Kastrati
Albert
A
Schömig
Thomas
T
Meitinger
Georg W
GW
Bornkamm
Marcus
M
Conrad
Nicolas
N
von Beckerath
D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000201:enzymology / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D005838:Genotype; D006579:Heterozygote; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology; D009154:Mutation / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D011487:Protein Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism; D054482:Thioredoxin Reductase 2 / Q000235:genetics*
D017382:Reactive Oxygen Species; C516127:TXNRD2 protein, human; D054482:Thioredoxin Reductase 2