| Summary: | Male infertility is a multifactorial disease with a strong genetic background. Abnormal sperm morphologies have been found to be closely related to male infertility. Here, we conducted whole-exome sequencing in a cohort of 150 Han Chinese men with asthenoteratozoospermia. Two novel hemizygous mutations were identified in <i>USP26</i>, an X-linked gene preferentially expressed in the testis and encoding a deubiquitinating enzyme. These <i>USP26</i> variants are extremely rare in human population genome databases and have been predicted to be deleterious by multiple bioinformatics tools. Hematoxylin-eosin staining and electron microscopy analyses of the spermatozoa from men harboring hemizygous <i>USP26</i> variants showed a highly aberrant morphology and ultrastructure of the sperm heads and flagella. Real-time quantitative PCR and immunoblotting assays revealed obviously reduced levels of <i>USP26</i> mRNA and protein in the spermatozoa from men harboring hemizygous deleterious variants of <i>USP26</i>. Furthermore, intracytoplasmic sperm injections performed on infertile men harboring hemizygous <i>USP26</i> variants achieved satisfactory outcomes. Overall, our study demonstrates that <i>USP26</i> is essential for normal sperm morphogenesis, and hemizygous <i>USP26</i> mutations can induce X-linked asthenoteratozoospermia. These findings will provide effective guidance for the genetic and reproductive counseling of infertile men with asthenoteratozoospermia.
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