Discovery of a Pathogenic <scp> <i>NME5</i> </scp> Variant Underlying Acephalic Spermatozoa Syndrome: Unraveling a Novel Genotype–Phenotype Association in Male Infertility

Acephalic spermatozoa syndrome (ASS) is a severe form of male infertility, but its genetic etiology remains largely unclear. In this study, we identified a novel homozygous frameshift variant in NME5 (c.163delA, p.Ser55Valfs*16) in an infertile man with ASS. Subsequent functional analyses revealed complete loss of NME5 protein. Moreover, ultrastructural analysis of sperm revealed abnormalities in the head-tail coupling apparatus (HTCA) and mitochondrial sheath, as well as defects in the radial spokes and microtubules. Immunofluorescence analysis further confirmed the near absence of the HTCA marker SPATA6 in the patient's sperm. In addition, NME5 expression was assessed across spermatogenic stages in both humans and mice, with predominant expression from round to elongated spermatids. Notably, the patient harboring the NME5 variant achieved a favorable clinical outcome after intracytoplasmic sperm injection. Overall, our findings revealed for the first time that NME5 is a causative gene for human ASS, further expanding the gene mutational spectrum associated with human male infertility and ultimately offering potential new avenues for diagnostic and therapeutic strategies in clinical practice.