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 in USP26, an X-linked gene preferentially expressed in the testis and encoding a deubiquitinating enzyme. These USP26 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 USP26 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 USP26 mRNA and protein in the spermatozoa from men harboring hemizygous deleterious variants of USP26. Furthermore, intracytoplasmic sperm injections performed on infertile men harboring hemizygous USP26 variants achieved satisfactory outcomes. Overall, our study demonstrates that USP26 is essential for normal sperm morphogenesis, and hemizygous USP26 mutations can induce X-linked asthenoteratozoospermia. These findings will provide effective guidance for the genetic and reproductive counseling of infertile men with asthenoteratozoospermia.
Highlights
Sperm biogenesis is a complex biological process that requires accurate spatio-temporal regulation of a list of specific genes; the absence of any important gene will lead to abnormal spermatogenesis [1]
Whole-exome sequencing analyses were performed on the cohort of 150 subjects affected by asthenoteratozoospermia, according to a previously described protocol [21]
After applying stringent bioinformatic analyses, we identified two men harboring hemizygous missense variants in USP26 (MIM: 300309): c.2473C>G
Summary
Sperm biogenesis is a complex biological process that requires accurate spatio-temporal regulation of a list of specific genes; the absence of any important gene will lead to abnormal spermatogenesis [1]. Asthenoteratozoospermia, an important factor leading to male infertility, has been defined as a disorder of genetic origin, and recurrent mutations have been identified in several specific phenotypes, including macrozoospermia, globozoospermia, and multiple morphological abnormalities of the flagella (MMAF). 22 MMAF-associated genes have been reported since the initial identification of DNAH1 [5,6,7,8,9,10]. All of these findings indicated the genetic heterogeneity of asthenoteratozoospermia and the potential involvement of other pathogenic factors
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
