Li Xueqi, Yu Haibing, Tang Xiangrong, Long Shunhua, Hu Tingwenyi, Ma Jing, Liu Guicen, Liu Xiaolin, Han Wei, Liu Weiwei, Liao Haiyuan, Huang Guoning, Wang Yingxiong, Lin Tingting
Centre for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Health Centre for Women and Children, Chongqing, China.
The Joint International Research Laboratory of Reproduction and Development of the Ministry of Education of China, Chongqing Medical University, Chongqing, China.
Reprod Biomed Online. 2025 Mar 20;51(2):104949. doi: 10.1016/j.rbmo.2025.104949.
What additional genetic mutations in DNAH2, DNAH6 and DNAH10 are linked to multiple morphological abnormalities of sperm flagella (MMAF), and what are the assisted reproductive outcomes in couples affected by these mutations?
A cohort of 75 infertile males with MMAF underwent whole-exome sequencing and Sanger sequencing to identify pathogenic mutations. Papanicolaou staining and electron microscopy were employed to evaluate sperm morphology and ultrastructure. Immunofluorescence was performed to characterize ultrastructural abnormalities at the molecular level, and explore the underlying molecular mechanisms by which mutations in DNAH2, DNAH6 and DNAH10 genes lead to MMAF.
Ten mutations were identified in six unrelated infertile males and were predicted to be pathogenic by bioinformatic tools. Papanicolaou staining and scanning electron microscopy showed that all the male patients harbouring mutations in the DNAH2, DNAH6 and DNAH10 loci displayed severe sperm morphological defects, predominantly characterized by the absence and reduced length of sperm flagella. Transmission electron microscopy (TEM) revealed substantial loss of inner dynein arms and mitochondrial damage, and immunofluorescence data further supported the findings of TEM and indicated a possible interaction between DNAH2 and DNAH10. Moreover, five out of six affected couples achieved a live birth via intracytoplasmic sperm injection (ICSI).
The data suggest that patients with DNAH2, DNAH6 and DNAH10 mutations causing severe asthenoteratozoospermia can achieve favourable outcomes through ICSI. These findings broaden the spectrum of DNAH2, DNAH6 and DNAH10 mutations, and provide valuable insights for future genetic counselling of infertile males with MMAF.
DNAH2、DNAH6和DNAH10中的哪些额外基因突变与精子鞭毛多发形态异常（MMAF）相关，以及受这些突变影响的夫妇辅助生殖结局如何？
对75名患有MMAF的不育男性队列进行全外显子组测序和桑格测序以鉴定致病突变。采用巴氏染色和电子显微镜评估精子形态和超微结构。进行免疫荧光以在分子水平表征超微结构异常，并探索DNAH2、DNAH6和DNAH10基因突变导致MMAF的潜在分子机制。
在6名无亲缘关系的不育男性中鉴定出10种突变，生物信息学工具预测这些突变具有致病性。巴氏染色和扫描电子显微镜显示，所有在DNAH2、DNAH6和DNAH10位点携带突变的男性患者均表现出严重的精子形态缺陷，主要特征为精子鞭毛缺失和长度缩短。透射电子显微镜（TEM）显示内动力蛋白臂大量缺失和线粒体损伤，免疫荧光数据进一步支持了TEM的结果，并表明DNAH2和DNAH10之间可能存在相互作用。此外，6对受影响的夫妇中有5对通过胞浆内单精子注射（ICSI）实现了活产。
数据表明，由DNAH2、DNAH6和DNAH10突变导致严重弱畸精子症的患者可通过ICSI获得良好结局。这些发现拓宽了DNAH2、DNAH6和DNAH10突变的范围，并为未来患有MMAF的不育男性的遗传咨询提供了有价值的见解。
