METTL5 deficiency induces oligoasthenoteratozoospermia via impaired 18S rRNA m6A methylation in humans and mice.

Recent studies have highlighted RNA modifications as integral regulators of gene expression during spermatogenesis. Ribosomal RNAs (rRNAs) are the most abundant RNA in the cells, while the function and clinical relevance of rRNA modifications in spermatogenesis remain poorly understood. Here, we identified 4 pathogenic heterozygous variants of METTL5 in 1427 patients with male infertility characterized as oligoasthenoteratozoospermia (OAT). The pathogenic variants of METTL5 led to the significantly decreased expression level of METTL5. Null-mutation of 18S rRNA methyltransferase Mettl5 led to male infertility attributed to oligoasthenoteratozoospermia (OAT) during spermiogenesis, presenting defects in both the sperm head and tail. Notwithstanding the absence of notable changes in global translation after Mettl5 loss, we observed a compromised translational efficiency of mRNAs encoding proteins crucial for spermiogenesis, including Gk2, Akap4, Fsip2, Odf2, and Pgk2. Intriguingly, therapeutic interventions via intra-cytoplasmic sperm injection (ICSI) in OAT couples with these variants resulted in successful pregnancies. These insights not only identify METTL5-mediated 18S rRNA m6A modification as a novel genetic determinant for OAT but also offer a new target to the genetic counseling, clinical diagnosis and potential treatment strategies for male infertility.