Further evidence from DNAH12 supports favorable fertility outcomes of infertile males with dynein axonemal heavy chain gene family variants

Hao Geng; Kai Wang; Dan Liang; Xiaoqing Ni; Hui Yu; Dongdong Tang; Mingrong Lv; Huan Wu; Kuokuo Li; Qunshan Shen; Yang Gao; Chuan Xu; Ping Zhou; Zhaolian Wei; Yunxia Cao; Yanwei Sha; Xiaoyu Yang; Xiaojin He

doi:10.1016/j.isci.2024.110366

Further evidence from DNAH12 supports favorable fertility outcomes of infertile males with dynein axonemal heavy chain gene family variants

iScience. 2024 Jun 24;27(7):110366. doi: 10.1016/j.isci.2024.110366. eCollection 2024 Jul 19.

Authors

Hao Geng^{1

2

3

4}, Kai Wang^{1

2}, Dan Liang^{2

3

4}, Xiaoqing Ni^{1

2}, Hui Yu^{1

2}, Dongdong Tang^{1

2

3

4}, Mingrong Lv^{1

2

3

4}, Huan Wu^{1

2

3

4}, Kuokuo Li^{1

2

3

4}, Qunshan Shen^{2

3

4}, Yang Gao^{1

2}, Chuan Xu^{1

2}, Ping Zhou^{1

2

3

4}, Zhaolian Wei^{1

2

3

4}, Yunxia Cao^{1

2

3

4}, Yanwei Sha⁵, Xiaoyu Yang⁶, Xiaojin He^{1

7

2}

Affiliations

¹ Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
² NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, Anhui, China.
³ Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China.
⁴ Anhui Province Key Laboratory of Reproductive Health and Genetics, Hefei, Anhui, China.
⁵ School of Public Health & Women and Children's Hospital, Xiamen University, Xiamen, Fujian, China.
⁶ State Key Laboratory of Reproductive Medicine and Offspring Health, The Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
⁷ Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

Male infertility is a major concern affecting reproductive health. Biallelic deleterious variants of most DNAH gene family members have been linked to male infertility, with intracytoplasmic sperm injection (ICSI) being an efficacious way to achieve offspring. However, the association between DNAH12 and male infertility is still limited. Here, we identified one homozygous variant and two compound heterozygous variants in DNAH12 from three infertile Chinese men. Semen analysis revealed severe asthenozoospermia, abnormal morphology, and structure of sperm flagella. Furthermore, the Dnah12 knock-out mouse revealed severe spermatogenesis failure and validated the same male infertility phenotype. Favorable fertility outcomes were achieved through ICSI in three human individuals and Dnah12 knock-out mice. Collectively, our study indicated that biallelic variants of DNAH12 can induce male infertility in both human beings and mice. Notably, evidence from DNAH12 enhanced that ICSI was an optimal intervention to achieve favorable fertility outcomes for infertile males with DNAH gene family variants.

Keywords: Genetics; Genomics; Human Genetics; Molecular biology; Reproductive medicine.