Male infertility remains a mystery in about 30% of cases. Recent studies by researchers at the University of California, San Diego School of Medicine reveal that a group of genes called RHOX play a crucial role in forming stem cells in the testes, cells essential for sperm production. The studies also connect mutations in these RHOX genes to infertility in men.
About 15% of couples worldwide face infertility, with nearly half of these cases due to male factors. That means roughly 7% of men of reproductive age—around 4 million in the U.S. alone—struggle with fertility problems, said Dr. Miles Wilkinson, a professor of reproductive medicine and lead researcher on the mouse study published in Cell Reports. The human genetic study appeared in Human Molecular Genetics and was led by Dr. Jörg Gromoll in Germany, with Wilkinson as co-author.
Sperm develop from cells passing through many stages, guided by proteins called transcription factors. Scientists have identified many factors controlling these stages but until now, none were known to control the vital step of forming spermatogonial stem cells—the stem cells in testes that produce sperm.
In their mouse study, Wilkinson’s team deleted all 33 Rhox genes and noticed a significant drop in these stem cells. Removing just one gene, Rhox10, caused a similar problem. The issue wasn’t that the stem cells were defective but that fewer of the precursor cells, called pro-spermatogonia, matured into stem cells. This shortage prevented the testes from growing and sperm counts from rising as the mice aged.
Rhox10 appears to be the key gene for this process, the researchers concluded.
Since Rhox genes are located on the X chromosome, mutations there can directly cause infertility in men, who have only one X chromosome and no backup copy. This discovery could help explain many cases of male infertility linked to X chromosome defects.
The findings also have clinical potential. For example, Rhox genes may be involved in testicular tumors that form when germ cells get stuck early in development. Additionally, these genes might aid future therapies using stem cells to restore fertility.
In the human study, Gromoll’s team sequenced RHOX genes in 250 men with very low sperm counts. They found several mutations in RHOXF1, RHOXF2, and RHOXF2B genes, with only one mutation appearing in men with normal sperm counts. Laboratory tests showed that some of these mutations reduce the function of RHOXF2/2B, changing the protein’s shape and impairing its ability to regulate genes.
Dr. Hye-Won Song, first author on both studies, emphasized the importance of spermatogonial stem cells in sperm production—even in older men. “Our research shows that Rhox10 is essential for these stem cells, and mutations in human RHOX genes likely cause male infertility,” she said.
Further supporting this link, previous research found abnormal chemical markers on RHOX genes in men with poor sperm quality. Wilkinson, Song, and their colleagues are now investigating how changes in RHOX transcription factors lead to infertility in men.
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