Scholarlink

Purpose <p>Severe asthenoteratozoospermia (ATZ) is a major cause of male infertility and is frequently associated with defects in sperm flagellar architecture. <i>DNAH12</i> encodes a dynein heavy chain of the inner dynein arm (IDA); however, the spectrum of sperm structural abnormalities associated with <i>DNAH12</i> mutations in humans remains incompletely characterized.</p> Methods <p>Whole-exome sequencing (WES) was performed in two infertile men with severe ATZ. Sperm from patients and fertile controls were examined by immunofluorescence (IF) staining for DNAH12 and related axonemal proteins, hematoxylin and eosin (H&amp;E) staining for sperm head and tail morphology, and transmission electron microscopy (TEM) for ultrastructural evaluation. The developmental expression pattern of DNAH12 was analyzed using integrated single-cell transcriptomic datasets. Intracytoplasmic sperm injection (ICSI) outcomes were assessed to evaluate reproductive potential.</p> Results <p>In this study, two novel homozygous loss-of-function (LoF) variants in <i>DNAH12</i> (c.5442dupT and c.6286C &gt; T) were identified. DNAH12 deficiency in patient sperm was accompanied by loss of DNAH1, DNALI1, RSPH9, and SPAG6 and disruption of the classical “9 + 2” axonemal structure. Although H&amp;E staining and TEM revealed marked abnormalities in both flagellar and head morphology, the acrosomal region and key functional markers of the sperm head remained preserved. Single-cell analyses showed stage-specific DNAH12 expression from secondary spermatocytes to round spermatids, consistent with roles in early flagellar assembly and sperm head morphogenesis. Both patients achieved normal fertilization and embryo development following ICSI.</p> Conclusions <p>These findings expand the DNAH12-related spectrum of male infertility and support ICSI as an effective reproductive option for affected individuals.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Biallelic loss-of-function variants in DNAH12 cause inner dynein arm defects and sperm head abnormalities leading to male infertility

  • 期刊论文

  • 发表日期：

    2026年6月19日

查看全文
  • Guotong Li,
  • Meizhou Liu,
  • Xing Zha,
  • Xun Xia,
  • Shikui Yin,
  • Yuqian Li,
  • Sana Atta,
  • Aylla Raja,
  • Qingsong Xie,
  • Sile Zou,
  • Yudie Guo,
  • Congyang Wang,
  • Rong Hua,
  • Yunxia Cao,
  • Huan Wu,
  • Yingchun Liu

摘要

Purpose

Severe asthenoteratozoospermia (ATZ) is a major cause of male infertility and is frequently associated with defects in sperm flagellar architecture. DNAH12 encodes a dynein heavy chain of the inner dynein arm (IDA); however, the spectrum of sperm structural abnormalities associated with DNAH12 mutations in humans remains incompletely characterized.

Methods

Whole-exome sequencing (WES) was performed in two infertile men with severe ATZ. Sperm from patients and fertile controls were examined by immunofluorescence (IF) staining for DNAH12 and related axonemal proteins, hematoxylin and eosin (H&E) staining for sperm head and tail morphology, and transmission electron microscopy (TEM) for ultrastructural evaluation. The developmental expression pattern of DNAH12 was analyzed using integrated single-cell transcriptomic datasets. Intracytoplasmic sperm injection (ICSI) outcomes were assessed to evaluate reproductive potential.

Results

In this study, two novel homozygous loss-of-function (LoF) variants in DNAH12 (c.5442dupT and c.6286C > T) were identified. DNAH12 deficiency in patient sperm was accompanied by loss of DNAH1, DNALI1, RSPH9, and SPAG6 and disruption of the classical “9 + 2” axonemal structure. Although H&E staining and TEM revealed marked abnormalities in both flagellar and head morphology, the acrosomal region and key functional markers of the sperm head remained preserved. Single-cell analyses showed stage-specific DNAH12 expression from secondary spermatocytes to round spermatids, consistent with roles in early flagellar assembly and sperm head morphogenesis. Both patients achieved normal fertilization and embryo development following ICSI.

Conclusions

These findings expand the DNAH12-related spectrum of male infertility and support ICSI as an effective reproductive option for affected individuals.