DNAH6, dynein axonemal heavy chain 6, is a crucial gene related to cilia function. It is part of the dynein complex in cilia, which is essential for ciliary motility. Motile cilia play significant roles in processes like left-right patterning during embryonic development and airway clearance, and thus DNAH6 is of great biological importance [3]. Genetic models, such as knockdown in zebrafish, can be used to study its functions.

Mutations in DNAH6 have been associated with multiple human disorders. In infertile men, DNAH6 mutations are linked to various sperm abnormalities. A novel homozygous frameshift mutation in DNAH6 was found in two brothers with asthenoteratozoospermia, leading to abnormal sperm morphology and ultrastructure, and abnormal gene expression [1]. Compound heterozygous variants in DNAH6 were identified in a patient with sperm head anomalies, where the protein was undetectable in the patient's spermatozoa [2]. DNAH6 mutations were also found in men with multiple morphological abnormalities of the sperm flagella (MMAF), with the protein localized in the sperm tail [4]. Moreover, in a study of 375 asthenoteratozoospermia patients, novel DNAH6 variants were associated with sperm head and flagella defects, and intracytoplasmic sperm injection (ICSI) was an effective treatment for such patients [6]. In addition, DNAH6 mutations can cause heterotaxy and ciliary dysfunction similar to primary ciliary dyskinesia (PCD), and trans-heterozygous interactions between DNAH6 and other PCD genes may cause heterotaxy [3]. Also, a significant null deletion of DNAH6 was observed in asthenozoospermia patients in India, indicating its impact on male infertility [5].

In conclusion, DNAH6 is essential for cilia-related functions and normal sperm development. Studies using genetic models and human patient samples have revealed its role in male infertility-related sperm abnormalities, as well as in heterotaxy and PCD-like ciliary dysfunctions. Understanding DNAH6's functions provides insights into the genetic etiologies of these diseases and may inform genetic and reproductive counseling and treatment strategies.

References:

1. Huang, Fei, Zeng, Jun, Liu, Dan, Song, Wanjuan, Huang, Hua-Lin. 2023. A novel frameshift mutation in DNAH6 associated with male infertility and asthenoteratozoospermia. In Frontiers in endocrinology, 14, 1122004. doi:10.3389/fendo.2023.1122004. https://pubmed.ncbi.nlm.nih.gov/37424858/

2. Li, L, Sha, Y-W, Xu, X, Yin, C, Li, P. 2018. DNAH6 is a novel candidate gene associated with sperm head anomaly. In Andrologia, , . doi:10.1111/and.12953. https://pubmed.ncbi.nlm.nih.gov/29356036/

3. Li, You, Yagi, Hisato, Onuoha, Ezenwa Obi, Tsang, Michael, Lo, Cecilia W. 2016. DNAH6 and Its Interactions with PCD Genes in Heterotaxy and Primary Ciliary Dyskinesia. In PLoS genetics, 12, e1005821. doi:10.1371/journal.pgen.1005821. https://pubmed.ncbi.nlm.nih.gov/26918822/

4. Tu, Chaofeng, Nie, Hongchuan, Meng, Lanlan, Lin, Ge, Tan, Yue-Qiu. 2019. Identification of DNAH6 mutations in infertile men with multiple morphological abnormalities of the sperm flagella. In Scientific reports, 9, 15864. doi:10.1038/s41598-019-52436-7. https://pubmed.ncbi.nlm.nih.gov/31676830/

5. Kumar, Dinesh, Jeena, Lalit Mohan, Tempe, Anjali, Tanwar, Renu, Kumar, Suman. 2024. Molecular characterization of DNAH6 and ATPase6 (Mitochondrial DNA) genes in asthenozoospermia patients in the northern region of India. In BMC urology, 24, 180. doi:10.1186/s12894-024-01505-9. https://pubmed.ncbi.nlm.nih.gov/39192248/

6. Shao, Zhong-Mei, Zhu, Yu-Tong, Gu, Meng, Xu, Yu-Ping, Lv, Ming-Rong. 2023. Novel variants in DNAH6 cause male infertility associated with multiple morphological abnormalities of the sperm flagella (MMAF) and ICSI outcomes. In Asian journal of andrology, 26, 91-98. doi:10.4103/aja202328. https://pubmed.ncbi.nlm.nih.gov/37594300/