Zmynd15, zinc finger MYND-type containing 15, acts as a histone deacetylase-dependent transcriptional repressor. It is essential for spermiogenesis, a key process in spermatogenesis where spermatids develop into spermatozoa. It controls the normal temporal expression of haploid cell genes during spermiogenesis, and its inactivation leads to early activation of important haploid genes, depletion of late spermatids, and male infertility [4].

In humans, mutations in Zmynd15 are associated with various male infertility conditions. A study of infertile Chinese men identified 31 Zmynd15 variants in 227 patients, with 3 deleterious biallelic variants in 3 individuals having oligoasthenoteratozoospermia, showing a biallelic pathogenic mutation frequency of 1.3% [1]. Another study found 3 novel homozygous truncating variants in Zmynd15 in 3 out of 219 infertile men with severe oligozoospermia (1.37%) [2]. Also, a homozygous loss-of-function variant in Zmynd15 was identified in a subject with severe oligozoospermia and a phenotypic diagnosis of macrozoospermia, suggesting that genetic defects in Zmynd15 can induce complete non-obstructive azoospermia (NOA) or severe oligozoospermia associated with very severe teratozoospermia [3]. Moreover, environmental pollutant sodium arsenite impairs sperm quality in male rats by reducing the expression of Zmynd15 and its regulatory genes [5].

In conclusion, Zmynd15 is crucial for normal spermiogenesis and male fertility. Studies on Zmynd15-related mutations in human male infertility, along with the understanding from its function as a transcriptional repressor in spermiogenesis, help in expanding the knowledge of male infertility mechanisms. These findings may potentially contribute to genetic counseling and diagnosis for male infertility cases [1,2,3,4,5].

References:

1. Wen, Yuting, Wang, Xiang, Zheng, Rui, Yang, Yihong, Shen, Ying. 2022. Sequencing of the ZMYND15 gene in a cohort of infertile Chinese men reveals novel mutations in patients with teratozoospermia. In Journal of medical genetics, 60, 380-390. doi:10.1136/jmg-2022-108727. https://pubmed.ncbi.nlm.nih.gov/35973810/

2. Hu, Tong-Yao, Zhang, Huan, Meng, Lan-Lan, Nie, Hong-Chuan, Tan, Yue-Qiu. 2020. Novel homozygous truncating variants in ZMYND15 causing severe oligozoospermia and their implications for male infertility. In Human mutation, 42, 31-36. doi:10.1002/humu.24138. https://pubmed.ncbi.nlm.nih.gov/33169450/

3. Kherraf, Zine-Eddine, Cazin, Caroline, Lestrade, Florence, Thierry-Mieg, Nicolas, Ray, Pierre F. . From azoospermia to macrozoospermia, a phenotypic continuum due to mutations in the ZMYND15 gene. In Asian journal of andrology, 24, 243-247. doi:10.4103/aja202194. https://pubmed.ncbi.nlm.nih.gov/35017390/

4. Yan, Wei, Si, Yue, Slaymaker, Sarah, Verdin, Eric, Charo, Israel F. 2010. Zmynd15 encodes a histone deacetylase-dependent transcriptional repressor essential for spermiogenesis and male fertility. In The Journal of biological chemistry, 285, 31418-26. doi:10.1074/jbc.M110.116418. https://pubmed.ncbi.nlm.nih.gov/20675388/

5. Li, Xiangli, Shen, Kaina, Yuan, Dunxuan, Zhang, Li, Wang, Junling. 2024. Sodium arsenite impairs sperm quality via downregulating the ZMYND15 and ZMYND10. In Environmental toxicology, 39, 4385-4396. doi:10.1002/tox.24327. https://pubmed.ncbi.nlm.nih.gov/38798119/