Scientists discover a new subtype of asthenospermia

The team of Wu Jianping, a distinguished researcher at the School of Life Sciences and Westlake Laboratory of Westlake University, together with the team of Gui Miao, a researcher at Zhejiang University, and Liu Mingxi, a professor at Nanjing Medical University, analyzed the cryo-EM structure of sperm flagellar microtubule binder complexes in mice and humans for the first time, identified multiple sperm-specific microtubule-binding proteins, and discovered a new subtype of asthenia.

The findings, published online on June 8 in Cell, provide important clues to understanding the structural basis of sperm motility and the diagnosis and treatment of related male infertility.

Comparison of microtubule structure of mouse and human sperm Photo courtesy of the research group

If sperm is a “car”, then flagella are the “engine” of the car, and once the “engine” fails, the “car” cannot start. By comparing human sperm flagellar microtubule diad with mouse sperm microtubule diplex, the research team clearly saw the differences between sperm microtubule diplex in different species. “The structure shows that MIP protein is a key component that affects the performance of the ‘engine’.” Wu Jianping said. 

In previous studies of male infertility, there have been relatively many studies on multiple morphological abnormalities of the sperm flagella (MMAF) caused by “morphological abnormalities”, and the sperm flagella of MMAF patients are “different” in appearance from normal sperm flagella. However, in the genetic screening of this type of patients with asthenospermia, no abnormalities in the MIP protein were detected, which did not seem to be consistent with the research team’s judgment. This discovery sparked the research team’s interest.

The research team recruited 281 non-MMAF male infertility patients whose sperm morphology did not look different from normal people, but whose motility was abnormal and could not complete normal fertilization. By performing exome sequencing analysis on these patients, the research team found that 32 of them carried mutations associated with MIP proteins, covering 10 MIP proteins, involving a total of 17 mutant forms, of which 8 MIP proteins were first found to be associated with male infertility.

The research team further found that the distribution of these mutation sites in the sperm microtubule diad is scattered, indicating that abnormalities in different regions of the microtubule diad may lead to the destruction of their own structure, which in turn causes abnormal sperm function. Therefore, the research team proposed a new subtype of azoospermia, called “MIP mutation-associated asthenospermia”. The common characteristics of sperm in this type of asthenospermia patients are impaired sperm motility, abnormal flagellar swing, and impaired axon structure, but no obvious defects in morphology.

Wu Jianping said that the results of this study have laid an important foundation for us to understand the specificity of microtubule dimorphs in different species and tissues, as well as to deeply study and understand the function and regulation of sperm flagella, providing new ideas for the diagnosis of related male infertility, and providing new ways for potential therapeutic interventions.

It is reported that Zhou Lunni, Liu Haobin, 2020 doctoral students of Westlake University, and Liu Siyu, a doctoral student of Nanjing Medical University, are the co-first authors of this paper. Wu Jianping, Gui Miao and Liu Mingxi are the co-corresponding authors of this paper. (Source: Wen Caifei, China Science News)

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