Abstract

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 inUSP26, an X-linked gene preferentially expressed in the testis and encoding a deubiquitinating enzyme. TheseUSP26variants 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 hemizygousUSP26variants showed a highly aberrant morphology and ultrastructure of the sperm heads and flagella. Real-time quantitative PCR and immunoblotting assays revealed obviously reduced levels ofUSP26mRNA and protein in the spermatozoa from men harboring hemizygous deleterious variants ofUSP26. Furthermore, intracytoplasmic sperm injections performed on infertile men harboring hemizygousUSP26variants achieved satisfactory outcomes. Overall, our study demonstrates thatUSP26is essential for normal sperm morphogenesis, and hemizygousUSP26mutations can induce X-linked asthenoteratozoospermia. These findings will provide effective guidance for the genetic and reproductive counseling of infertile men with asthenoteratozoospermia.Keywords:male infertility;asthenoteratozoospermia;USP26;intracytoplasmic sperm injections