The strongest quantitative trait locus (QTL) modifying electrocardiographic QT interval has been mapped to human chromosome 1q23.3 by genome-wide association studies. Two genes from the region, NOS1AP (CAPON) and cardiomedin (OLFML2B) were investigated for their influence on cardiac repolarization and sudden death. Knockdown of both genes in zebrafish induced cardiac dilatation and arrhythmia. Cardiomedin missense mutations P504L, G515E and Y557H were found in three children affected by sudden infant death syndrome (SIDS). All three mutations suppressed cellular export of the secreted cardiomedin glycoprotein and led to significant IKr reductions when expressed in Xenopus laevis oocytes suggesting that cardiomedin mutations predispose to SIDS by decreasing myocardial repolarization reserve. Massspectrometry analysis of possible interaction partners of cardiomedin revealed proteins of the extra cellular matrix (ECM) like fibronectin and matrillin.
NOS1AP mutations were not observed in the patient sample. Identifying a novel monogenic disease gene and pathomechanism contributing to SIDS, we illuminate novel functional properties of the olfactomedin class of proteins providing an example how regional genes from different pathways may independently contribute to a quantitative trait locus.
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. 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. 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.
