Txndc2, a thioredoxin domain-containing protein, is involved in regulating the redox status. The thioredoxin system plays a crucial role in maintaining cellular redox homeostasis, which is essential for various biological processes such as cell growth, differentiation, and apoptosis [2].

In mice, functional deletion of Txndc2 along with Txndc3 did not impact spermatogenesis, epididymal sperm maturation, or fertility overall. However, it led to age-dependent changes in spermatozoa, including accelerated motility loss, high rates of DNA damage, increased reactive oxygen species generation, enhanced formation of lipid aldehyde-protein adducts, and impaired protamination of the sperm chromatin. This indicates that Txndc2 is important in protecting spermatozoa against age-related oxidative stress [2].

In humans, a homozygous deletion in TXNDC2 was identified in azoospermia patients from consanguineous Pakistani families, suggesting its potential pathogenic relevance to male infertility [3]. Also, combined analysis of TXNDC2 with PRM1 and PRM2 genes showed a high sensitivity (96.8%) and specificity (95.5%) in predicting sperm retrieval and correlating with severe azoospermia pathology [1].

In conclusion, Txndc2 is critically important in protecting spermatozoa from oxidative stress, especially related to paternal age. Research on Txndc2, including through gene-knockout mouse models, has provided insights into male infertility, particularly azoospermia, highlighting its potential as a biomarker for sperm retrieval and a key factor in understanding the molecular mechanisms underlying this form of male infertility [1,2,3].

References:

1. Javadirad, Seyed-Morteza, Mokhtari, Mohammad. 2021. TXNDC2 joint molecular marker is associated with testis pathology and is an accurate predictor of sperm retrieval. In Scientific reports, 11, 13064. doi:10.1038/s41598-021-92603-3. https://pubmed.ncbi.nlm.nih.gov/34158577/

2. Smith, T B, Baker, M A, Connaughton, H S, Habenicht, U, Aitken, R J. 2013. Functional deletion of Txndc2 and Txndc3 increases the susceptibility of spermatozoa to age-related oxidative stress. In Free radical biology & medicine, 65, 872-881. doi:10.1016/j.freeradbiomed.2013.05.021. https://pubmed.ncbi.nlm.nih.gov/23707457/

3. Uddin, Islam, Zafar, Iqra, Xu, Caoling, Wu, Limin, Bao, Jianqiang. 2024. Whole-exome sequencing identifies rare recessive variants in azoospermia patients from consanguineous Pakistani families. In Molecular genetics and genomics : MGG, 299, 111. doi:10.1007/s00438-024-02205-7. https://pubmed.ncbi.nlm.nih.gov/39625557/