Biallelic Variants in ATP1A4 Are Associated with Oligoasthenoteratozoospermia and Male Infertility.

Yantong Zheng; Yingteng Zhang; Keyu Ren; Chuan Jiang; Yihong Yang; Yunchuan Tian; Di Ouyang; Xiang Wang; Ying Shen

doi:10.1111/cge.70205

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Biallelic Variants in ATP1A4 Are Associated with Oligoasthenoteratozoospermia and Male Infertility.

Yantong Zheng·Yingteng Zhang·Keyu Ren·Chuan Jiang·Yihong Yang·Yunchuan Tian·Di Ouyang·Xiang Wang·Ying Shen

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Abstract

Male infertility, often caused by structural and functional sperm defects, remains genetically unexplained in a substantial proportion of cases. ATP1A4 encodes a testis-specific isoform of the Na+, K+-ATPase, a membrane enzyme crucial for maintaining cellular ionic homeostasis. Previous studies on Atp1a4 knockout mice have demonstrated severe defects in sperm motility and flagellar architecture; however, the contribution of ATP1A4 variants to human male reproduction remains to be elucidated. In this study, we identified compound biallelic variants in ATP1A4, a missense variant (c.2578 T>A, p.Tyr860Asn) and a frameshift variant (c.2582del, p.Gly861Aspfs*5), in a patient presenting with severe oligoasthenoteratozoospermia. Both variants markedly affected ATP1A4 protein expression. Morphological analyses revealed coiled and folded flagella, disrupted mitochondrial sheaths, and irregular head morphology in the patient's spermatozoa. Expression profiling revealed that ATP1A4 was highly enriched in post-meiotic spermatids and localized along the entire flagellum of mature sperm in both humans and mice, indicating a critical role in flagellar assembly and structural integrity. Notably, intracytoplasmic sperm injection (ICSI) in this patient resulted in low fertilization efficiency and failed implantation, suggesting a potential adverse impact of ATP1A4 deficiency on sperm functional competence beyond motility. These findings broaden the genetic spectrum of oligoasthenoteratozoospermia and highlight ATP1A4 as a potential gene associated with human male infertility.

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Male Humans Sodium-Potassium-Exchanging ATPase Infertility, Male Animals Mice Asthenozoospermia Spermatozoa Sperm Motility Oligospermia Alleles Genetic Predisposition to Disease ATP1A4 ICSI flagellar structure male infertility oligoasthenoteratozoospermia Journal Article

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Yantong Zheng, Yingteng Zhang, Keyu Ren, Chuan Jiang, Yihong Yang, Yunchuan Tian, Di Ouyang, Xiang Wang, Ying Shen. 2026-07-01. Biallelic Variants in ATP1A4 Are Associated with Oligoasthenoteratozoospermia and Male Infertility.. https://doi.org/10.1111/cge.70205

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Journal Article resource Alleles subject Animals subject Genetic Predisposition to Disease subject Humans subject Infertility, Male subject Journal Article subject Male subject Male infertility subject Mice subject

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