Pathological infertility affects around 7% of men, with 10-15% of cases believed to have a genetic origin. Despite this, identifying the exact genes responsible has proven challenging due to the many genes involved in sperm cell production and development.
A new study published in Science Signaling by a Japanese research team sheds light on one cause of infertility: incomplete development of proteins that package DNA in sperm cells. The team has made a breakthrough by successfully making infertile mice fertile again by altering just one amino acid in a critical protein.
In every cell, DNA is tightly wound around proteins called ‘histones.’ In sperm cells—the smallest cells in the human body—another protein, ‘protamine,’ is essential for wrapping the DNA even more tightly. This tight packing is crucial for sperm function.
Katsuhiko Itoh, the first author from Kyoto University’s Graduate School of Medicine, explains, “For about 30 years, we’ve known that protamines undergo modifications during sperm development to ensure they function properly. This led us to investigate the underlying mechanism of protamine regulation and how it affects sperm production, or spermatogenesis.”
The team focused on chaperones, proteins that assist in processing other proteins. Through genetic analysis, they discovered that one chaperone, Hspa4l, plays a critical role in sperm cell development. Dysfunction in this protein had similar effects to a deficiency in a gene called Ppp1cc2, which is involved in regulating other proteins.
Itoh continues, “We found that Hspa4l is crucial for the proper functioning of Ppp1cc2, a phosphatase. When Hspa4l malfunctions, Ppp1cc2 can’t reach the chromatin, which leads to the failure to dephosphorylate protamine 2 at serine 56. Without this modification, protamine 2 doesn’t work properly, preventing sperm cells from developing.”
Using these findings, the researchers created a mouse model with a single amino acid change: they replaced serine 56 with alanine, mimicking a non-phosphorylated state. This small alteration restored fertility in the mice, even with a mutation that made Hspa4l non-functional. The mice showed no issues with sperm production, indicating preserved fertility.
Itoh emphasizes the importance of understanding how protamine modifications impact sperm maturation. The research team hopes to continue exploring the complex interactions between genes and proteins in sperm development, potentially offering new insights into infertility treatments.
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