TXNRD2 – Dilated Cardiomyopathy

The association between TXNRD2 and Dilated Cardiomyopathy is classified as Strong by ClinGen due to evidence from five unrelated probands, functional concordance, and animal models. Genetic screening of 227 DCM patients identified two novel heterozygous missense variants in three individuals (c.175G>A and c.1123G>A) not seen in 683 controls (PMID:21247928). A neonatal fatal DCM case in a mother–infant pair carrying c.1054C>A (p.Pro352Thr) and an adolescent DCM proband with a concurrent DES variant further support pathogenicity (PMID:32257832, PMID:37465804). Functional studies demonstrate a dominant-negative mechanism impairing thioredoxin reductase 2 activity and a cardiac-specific Txnrd2 knockout mouse recapitulating the DCM phenotype.

Inheritance is Autosomal dominant, consistent with heterozygous missense variants exhibiting dominant-negative effects. Segregation data are limited, with no additional DCM-affected relatives beyond the probands. Across studies, five probands harbored missense substitutions within conserved FAD-binding helices; the prototypical variant c.175G>A (p.Ala59Thr) exemplifies this spectrum.

Functional assays reveal that neither mutant enzyme restores redox activity in Txnrd2–/– mouse fibroblasts and that expression of patient variants exacerbates oxidative-stress–induced cell death. Cardiac-specific Txnrd2 knockout mice develop left ventricular dilation and systolic dysfunction concordant with human DCM, demonstrating mechanistic alignment with a dominant-negative loss-of-function paradigm.

No conflicting reports have emerged disputing the TXNRD2–DCM link. Alternative phenotypes (e.g., peripartum cardiomyopathy) occur in mutation carriers but align with a shared mitochondrial redox defect rather than refuting the DCM association.

Collectively, genetic and experimental data support TXNRD2 as a causative gene for autosomal dominant dilated cardiomyopathy. Incorporation of TXNRD2 into DCM gene panels can enhance diagnostic yield, guide family screening, and inform potential antioxidant-based therapeutic strategies. Key Take-home: TXNRD2 heterozygous missense variants cause a dominant-negative disruption of mitochondrial redox homeostasis leading to dilated cardiomyopathy.

References

• European Heart Journal • 2011 • Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy. PMID:21247928
• Case Reports in Women’s Health • 2020 • Did a shared thioredoxin-reductase gene mutation lead to maternal peripartum cardiomyopathy and fatal dilated cardiomyopathy in her son? A case report. PMID:32257832
• Cureus • 2023 • A Rare Case of Coexisting Mutation in Desmin and Thioredoxin Reductase 2 Genes Causing Dilated Cardiomyopathy. PMID:37465804

Evidence Based Scoring (AI generated)