Novel variants in DNAH6 cause male infertility associated with multiple morphological abnormalities of the sperm flagella (MMAF) and ICSI outcomes.

IF 3 2区 医学 Q2 ANDROLOGY
Asian Journal of Andrology Pub Date : 2024-01-01 Epub Date: 2023-08-11 DOI:10.4103/aja202328
Zhong-Mei Shao, Yu-Tong Zhu, Meng Gu, Sen-Chao Guo, Hui Yu, Kuo-Kuo Li, Dong-Dong Tang, Yu-Ping Xu, Ming-Rong Lv
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引用次数: 0

Abstract

Variations in the dynein axonemal heavy chain gene, dynein axonemal heavy chain 6 ( DNAH6 ), lead to multiple morphological abnormalities of the flagella. Recent studies have reported that these deficiencies may result in sperm head deformation. However, whether DNAH6 is also involved in human acrosome biogenesis remains unknown. The purpose of this study was to investigate DNAH6 gene variants and their potential functions in the formation of defective sperm heads and flagella. Whole-exome sequencing was performed on a cohort of 375 patients with asthenoteratozoospermia from the First Affiliated Hospital of Anhui Medical University (Hefei, China). Hematoxylin and eosin staining, scanning electron microscopy, and transmission electron microscopy were performed to analyze the sperm morphology and ultrastructure. Immunofluorescence staining and Western blot analysis were conducted to examine the effects of genetic variants. We identified three novel deleterious variants in DNAH6 among three unrelated families. The absence of inner dynein arms and radial spokes was observed in the sperm of patients with DNAH6 variants. Additionally, deficiencies in the acrosome, abnormal chromatin compaction, and vacuole-containing sperm heads were observed in these patients with DNAH6 variants. The decreased levels of the component proteins in these defective structures were further confirmed in sperm from patients with DNAH6 variants using Western blot. After intracytoplasmic sperm injection (ICSI) treatment, the partner of one patient with a DNAH6 variant achieved successful pregnancy. Overall, novel variants in DNAH6 genes that contribute to defects in the sperm head and flagella were identified, and the findings indicated ICSI as an effective clinical treatment for such patients.

DNAH6的新型变体会导致与精子鞭毛多种形态异常(MMAF)和ICSI结果相关的男性不育症。
动力蛋白轴丝重链基因(动力蛋白轴丝重链 6,DNAH6)的变异会导致鞭毛的多种形态异常。最近的研究报告称,这些缺陷可能导致精子头部变形。然而,DNAH6是否也参与人类顶体生物发生仍是未知数。本研究旨在调查DNAH6基因变异及其在精子头部和鞭毛缺陷形成过程中的潜在功能。研究人员对安徽医科大学第一附属医院(中国合肥)的375名弱精症患者进行了全基因组测序。对精子的形态和超微结构进行了血红素和伊红染色、扫描电子显微镜和透射电子显微镜分析。免疫荧光染色和 Western 印迹分析用于检测基因变异的影响。我们在三个无血缘关系的家庭中发现了DNAH6的三个新的有害变异。在DNAH6变异体患者的精子中观察到缺乏内动力臂和径向辐条。此外,在这些DNAH6变异体患者的精子中还观察到顶体缺陷、染色质压实异常和含液泡的精子头部。使用 Western 印迹法进一步证实了 DNAH6 变异患者精子中这些缺陷结构的组成蛋白水平降低。经过卵胞浆内单精子注射(ICSI)治疗后,一名DNAH6变异体患者的伴侣成功怀孕。总之,鉴定出了导致精子头部和鞭毛缺陷的DNAH6基因新变异,研究结果表明卵胞浆内单精子注射是治疗此类患者的有效临床方法。
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来源期刊
Asian Journal of Andrology
Asian Journal of Andrology 医学-泌尿学与肾脏学
CiteScore
4.90
自引率
3.40%
发文量
2252
审稿时长
2.2 months
期刊介绍: Fields of particular interest to the journal include, but are not limited to: -Sperm biology: cellular and molecular mechanisms- Male reproductive system: structure and function- Hormonal regulation of male reproduction- Male infertility: etiology, pathogenesis, diagnosis, treatment and prevention- Semen analysis & sperm functional assays- Sperm selection & quality and ART outcomes- Male sexual dysfunction- Male puberty development- Male ageing- Prostate diseases- Operational andrology- HIV & male reproductive tract infection- Male contraception- Environmental, lifestyle, genetic factors and male health- Male reproductive toxicology- Male sexual and reproductive health.
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