Navapour Leila, Mogharrab Navid, Parvin Ali, Rezaei Arablouydareh Sahar, Movahedpour Ahmad, Jebraeily Mohamad, Taheri-Anganeh Mortaza, Ghasemnejad-Berenji Hojat
Reproductive Health Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
Biophysics and Computational Biology Laboratory (BCBL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran.
J Appl Genet. 2025 May;66(2):333-346. doi: 10.1007/s13353-024-00884-x. Epub 2024 Jun 14.
Male infertility is a significant reproductive issue affecting a considerable number of couples worldwide. While there are various causes of male infertility, genetic factors play a crucial role in its development. We focused on identifying and analyzing the high-risk nsSNPs in DNAH1 and DNAH17 genes, which encode proteins involved in sperm motility. A total of 20 nsSNPs for DNAH1 and 10 nsSNPs for DNAH17 were analyzed using various bioinformatics tools including SIFT, PolyPhen-2, CADD, PhD-SNPg, VEST-4, and MutPred2. As a result, V1287G, L2071R, R2356W, R3169C, R3229C, E3284K, R4096L, R4133C, and A4174T in DNAH1 gene and C1803Y, C1829Y, R1903C, and L3595P in DNAH17 gene were identified as high-risk nsSNPs. These nsSNPs were predicted to decrease protein stability, and almost all were found in highly conserved amino acid positions. Additionally, 4 nsSNPs were observed to alter post-translational modification status. Furthermore, the interaction network analysis revealed that DNAH1 and DNAH17 interact with DNAH2, DNAH3, DNAH5, DNAH7, DNAH8, DNAI2, DNAL1, CFAP70, DNAI3, DNAI4, ODAD1, and DNAI7, demonstrating the importance of DNAH1 and DNAH17 proteins in the overall functioning of the sperm motility machinery. Taken together, these findings revealed the detrimental effects of identified high-risk nsSNPs on protein structure and function and highlighted their potential relevance to male infertility. Further studies are warranted to validate these findings and to elucidate the underlying mechanisms.
男性不育是一个重大的生殖问题，影响着全球相当数量的夫妇。虽然男性不育有多种原因，但遗传因素在其发病过程中起着关键作用。我们专注于识别和分析DNAH1和DNAH17基因中的高风险非同义单核苷酸多态性（nsSNPs），这两个基因编码参与精子运动的蛋白质。使用包括SIFT、PolyPhen - 2、CADD、PhD - SNPg、VEST - 4和MutPred2在内的各种生物信息学工具，对DNAH1的20个nsSNPs和DNAH17的10个nsSNPs进行了分析。结果，DNAH1基因中的V1287G、L2071R、R2356W、R3169C、R3229C、E3284K、R4096L、R4133C和A4174T以及DNAH17基因中的C1803Y、C1829Y、R1903C和L3595P被鉴定为高风险nsSNPs。这些nsSNPs预计会降低蛋白质稳定性，并且几乎所有都位于高度保守的氨基酸位置。此外，观察到4个nsSNPs会改变翻译后修饰状态。此外，相互作用网络分析表明，DNAH1和DNAH17与DNAH2、DNAH3、DNAH5、DNAH7、DNAH8、DNAI2、DNAL1、CFAP70、DNAI3、DNAI4、ODAD1和DNAI7相互作用，证明了DNAH1和DNAH17蛋白在精子运动机制整体功能中的重要性。综上所述，这些发现揭示了已鉴定的高风险nsSNPs对蛋白质结构和功能的有害影响，并突出了它们与男性不育的潜在相关性。有必要进行进一步的研究来验证这些发现并阐明潜在机制。
