Biallelic Pathogenic Variants in DNAH3 Cause Asthenoteratozoospermia and Male Infertility in Humans and Mice

Core Concepts

Biallelic pathogenic variants in DNAH3, an inner dynein arm-associated protein, disrupt sperm flagellar development and lead to asthenoteratozoospermia and male infertility in humans and mice.

Abstract

This study identified biallelic pathogenic variants in the DNAH3 gene in four unrelated infertile men with asthenoteratozoospermia, a common phenotype of male infertility. The DNAH3 variants resulted in the absence of DNAH3 expression and decreased levels of other inner dynein arm-associated proteins, including DNAH1, DNAH6, and DNALI1, in the patients' sperm flagella. The sperm from these patients exhibited severe structural defects in the flagella, such as absent, short, coiled, bent, and irregular flagella, as well as disrupted ultrastructure of the "9+2" microtubule arrangement. Similarly, Dnah3 knockout male mice were also infertile, displaying severely reduced sperm motility and abnormal inner dynein arm and mitochondrial structure in the flagella. Importantly, intracytoplasmic sperm injection (ICSI) treatment was successful in two out of the four DNAH3-deficient patients and Dnah3 knockout mice, suggesting ICSI as a potential treatment option for male infertility caused by DNAH3 deficiency. The findings of this study demonstrate that DNAH3 is a novel pathogenic gene for asthenoteratozoospermia and male infertility, and provide insights into the genetic basis and potential clinical management of this condition.

Stats

Semen analysis revealed extremely reduced sperm motility and a high proportion of sperm tail defects in the patients. Sperm from the patients showed absent or disordered central pair, microtubule doublets, and outer dense fibers, as well as a clear absence of inner dynein arms. Dnah3 knockout male mice displayed severely reduced sperm motility and abnormal inner dynein arm and mitochondrial structure in the flagella.

Quotes

"Biallelic variants in DNAH3 in four unrelated Han Chinese infertile men with asthenoteratozoospermia through whole-exome sequencing (WES)." "Dnah3 knockout (KO) male mice were also infertile, especially showing the severe reduction in sperm movement with the abnormal IDA and mitochondrion structure." "The infertility of patients with DNAH3 variants and Dnah3 KO mice could be rescued by intracytoplasmic sperm injection (ICSI) treatment."

Key Insights Distilled From

Biallelic pathogenic variants in DNAH3 cause male infertility in humans and mice

by Wang,X., She... at www.biorxiv.org 02-21-2024

https://www.biorxiv.org/content/10.1101/2024.02.19.580977v1

Deeper Inquiries

How might the specific DNAH3 variants or other genetic factors influence the success rate of ICSI treatment in DNAH3-deficient patients?

The specific DNAH3 variants identified in the study led to a complete absence of DNAH3 expression in the sperm flagella of the patients. This deficiency in DNAH3 expression resulted in disrupted sperm motility, abnormal flagellar structure, and a high proportion of sperm tail defects. These factors can significantly impact the success rate of ICSI treatment in DNAH3-deficient patients. ICSI relies on the injection of a single sperm directly into an egg to achieve fertilization. In the case of DNAH3 deficiency, where sperm motility is severely compromised, the ability of the sperm to reach and fertilize the egg may be impaired. The abnormal flagellar structure and reduced sperm motility can hinder the sperm's ability to penetrate the egg and successfully fertilize it during the ICSI procedure. Additionally, the absence of DNAH3 may lead to deficiencies in other inner dynein arm (IDA)-associated proteins, such as DNAH1, DNAH6, and DNALI1, which are crucial for sperm motility. These deficiencies can further impact the functionality of the sperm and reduce the likelihood of successful fertilization during ICSI. Other genetic factors, in combination with DNAH3 variants, may also play a role in influencing the success rate of ICSI treatment. Variants in genes related to sperm function, flagellar structure, or fertilization capacity could interact with DNAH3 variants to exacerbate the infertility phenotype and reduce the effectiveness of ICSI treatment in these patients.

How might the specific DNAH3 variants or other genetic factors influence the success rate of ICSI treatment in DNAH3-deficient patients?

In the absence of DNAH3, which plays a crucial role in sperm flagellar development and motility, identifying potential compensatory mechanisms or alternative pathways to restore sperm motility and flagellar structure is essential. Several strategies could be explored to address these challenges: Targeting IDA-Associated Proteins: Since DNAH3 deficiency leads to decreased expression of IDA-associated proteins like DNAH1, DNAH6, and DNALI1, targeting these proteins or pathways involved in their regulation could potentially restore flagellar structure and sperm motility. Modulating the expression or function of these proteins through gene therapy, pharmacological interventions, or other approaches could be explored. Enhancing Mitochondrial Function: The disrupted mitochondria observed in spermatozoa from DNAH3-deficient patients and Dnah3 KO mice suggest impaired mitochondrial function. Restoring mitochondrial health and energy production could improve sperm motility and overall fertility. Targeting mitochondrial pathways or introducing mitochondrial supplements could be potential strategies to address this issue. Stimulating Ciliary Development: Given the expression of DNAH3 in ciliated tissues beyond the testis, promoting ciliary development and function could have broader implications for restoring sperm motility. Understanding the mechanisms involved in ciliary development and exploring ways to enhance ciliary function in sperm cells could be beneficial in the absence of DNAH3. Exploring Signaling Pathways: Investigating signaling pathways involved in sperm motility and flagellar development could uncover potential targets for intervention. Targeting signaling molecules or pathways that regulate these processes could offer new avenues for restoring sperm function in DNAH3-deficient individuals. By targeting these compensatory mechanisms or alternative pathways, it may be possible to restore sperm motility and flagellar structure in the absence of DNAH3, ultimately improving the success rate of fertility treatments like ICSI in DNAH3-deficient patients.

How might the specific DNAH3 variants or other genetic factors influence the success rate of ICSI treatment in DNAH3-deficient patients?

The expression of DNAH3 in ciliated tissues beyond the testis suggests broader implications for human health and disease beyond male infertility. Understanding the role of DNAH3 in ciliary function and motility in other tissues could provide insights into various health conditions and diseases. Respiratory Health: Given the involvement of DNAH3 in ciliary function, its deficiency could impact respiratory health. Ciliary dysfunction in the lungs can lead to conditions like primary ciliary dyskinesia (PCD) and respiratory infections. Understanding the role of DNAH3 in respiratory cilia could shed light on the pathogenesis of respiratory diseases. Neurological Disorders: Ciliary dysfunction in the brain can contribute to neurological disorders. DNAH3 variants may influence ciliary function in the brain, affecting processes like cerebrospinal fluid flow and neuronal signaling. Investigating the role of DNAH3 in brain cilia could provide insights into conditions like hydrocephalus and neurodevelopmental disorders. Oviduct Function: Ciliary dysfunction in the oviduct can impact female fertility and reproductive health. DNAH3 expression in ciliated tissues of the oviduct may play a role in embryo transport and fertilization. Understanding the implications of DNAH3 deficiency in the oviduct could have implications for female infertility and reproductive disorders. Ciliopathies: DNAH3 deficiency could contribute to a spectrum of ciliopathies, which are genetic disorders affecting cilia structure and function. Exploring the role of DNAH3 in ciliary biology could provide insights into the pathogenesis of various ciliopathies and inform potential therapeutic strategies. By investigating the broader implications of DNAH3 deficiency in ciliated tissues, researchers can gain a deeper understanding of ciliary function in health and disease. This knowledge could lead to advancements in the diagnosis, treatment, and management of conditions related to ciliary dysfunction and provide new avenues for therapeutic interventions.