Novel Mutations in X-Linked, -Induced Asthenoteratozoospermia and Male Infertility.

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 , an X-linked gene preferentially expressed in the testis and encoding a deubiquitinating enzyme. These 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 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 mRNA and protein in the spermatozoa from men harboring hemizygous deleterious variants of . Furthermore, intracytoplasmic sperm injections performed on infertile men harboring hemizygous variants achieved satisfactory outcomes. Overall, our study demonstrates that is essential for normal sperm morphogenesis, and hemizygous mutations can induce X-linked asthenoteratozoospermia. These findings will provide effective guidance for the genetic and reproductive counseling of infertile men with asthenoteratozoospermia.