A severe form of male infertility, known as azoospermia, affects about 1% of men and is responsible for roughly one-sixth of male infertility cases. Men with azoospermia do not produce measurable levels of sperm, and often, the cause of this condition remains unknown. However, new research from the University of Pennsylvania suggests that mutations in a gene called TEX11 on the X chromosome may be responsible for a significant number of these infertility cases, possibly up to 1% of non-obstructive azoospermia cases.
The study, published in EMBO Molecular Medicine, was led by P. Jeremy Wang, a professor at the University of Pennsylvania’s School of Veterinary Medicine. Wang’s team collaborated with researchers from various institutions, including St. Luke’s Hospital in St. Louis and the Massachusetts Institute of Technology.
This research builds on work Wang and his colleagues began 15 years ago. In 2008, they discovered that disrupting the TEX11 gene in mice caused sterility in males and reduced litter sizes in females. TEX11 is specific to germ cells and plays a key role in meiosis, the process that divides genetic material into eggs and sperm.
To explore the gene’s impact on human infertility, Wang’s team analyzed genetic samples from 246 men with azoospermia and compared them to control samples. They found more genetic variations in TEX11 among the men with azoospermia, suggesting that the gene plays an important role in sperm development.
The researchers also identified a man with a mutation in TEX11 who had a strong family history of infertility. Both he and his brother were azoospermic, and genetic testing revealed that their mother carried the mutation. Although the researchers could not confirm whether the man’s maternal uncles shared the same mutation, the pattern suggested that the condition was inherited through the maternal line via the X chromosome.
To test whether these mutations directly caused infertility, the team engineered mice with versions of TEX11 that carried the same mutations. They observed that while two of the mutations had little effect, one mutation caused significant infertility. Males with this mutation had lower sperm counts and abnormalities in meiosis.
The study concluded that three mutations in the TEX11 gene were linked to infertility in the men they studied, accounting for about 1% of azoospermia cases. Wang emphasized the significance of this finding, noting that while there are many candidate genes for male infertility, discovering a gene responsible for even 1% of cases is a major step forward.
As personalized medicine continues to advance, this discovery could have important implications for genetic counseling for men facing infertility. “If a man carries one of these mutations, we can confidently say that it’s the cause of his infertility,” Wang said.
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