The X-linked gene Luzp4 is dispensable for male fertility but contributes to normal spermatogenesis in mice
Genetic defects governing sperm flagellar assembly remain a major cause of idiopathic male infertility. Here, we identified a novel hemizygous variant in the X-linked gene LUZP4 in an infertile patient presenting with asthenoteratozoospermia and short sperm tails. To elucidate the physiological function of LUZP4, we generated a knockout mouse model. Although Luzp4-deficient mice did not exhibit the overt flagellar fractures observed in the human subject, they displayed a specific impairment in rapid progressive motility and exhibited compromised fertilization efficiency both in vivo and in vitro. Strikingly, this fertilization defect was rescued when using zona-free oocytes, suggesting that insufficient propulsive force-rather than a primary gamete recognition defect-limits fertilization. Ultrastructural analysis revealed that Luzp4 deficiency disrupts the integrity of the sperm annulus, causing the retraction and slippage of the mitochondrial sheath along the axoneme. Mechanistically, LUZP4 is implicated in the mRNA export pathway, and its absence leads to the specific depletion of transcripts encoding the annulus components, Septin4 and Septin12, thereby compromising annulus integrity and destabilizing the mitochondrial sheath. In response to this structural and motility deficit, spermatids markedly upregulate mitochondrial electron transport chain (ETC) components, including Complex I and IV subunits, and exhibit enhanced cytochrome c oxidase activity. However, this metabolic reprogramming fails to restore intracellular ATP, indicating that the energetic response is futile compensation. Collectively, our findings establish LUZP4 as an mRNA-export-linked regulator of septin-dependent annulus assembly, providing a mechanistic basis for impaired sperm propulsion and highlighting LUZP4 as a candidate gene for human male infertility.