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New study uncovers underlying reason for male infertility



New research is shedding light on one of the underlying causes of male infertility, paving the way for potential new treatments.

Millions of couples worldwide experience infertility with half of the cases originating in men. For 10% of infertile males, little or no sperm are produced. 

Research from the Stowers Institute for Medical Research, in collaboration with the Wellcome Centre for Cell Biology at the University of Edinburgh, is exploring what may be going wrong in the process of sperm formation, leading to potential theories on possible treatments.

“A significant cause of infertility in males is that they just cannot make sperm,” said Stowers Investigator, Scott Hawley PhD. 

“If you know exactly what is wrong, there are technologies emerging right now that might give you a way to fix it.”

The study published this month in Science Advances may help explain why some men do not make enough sperm to fertilise an egg. 

In most sexually reproducing species, including humans, a critical protein structure resembling a lattice-like bridge needs to be built properly to produce sperm and egg cells. 

The team led by former Postdoctoral Research Associate Katherine Billmyre PhD, discovered that in mice, changing a single and very specific point in this bridge caused it to collapse, leading to infertility and thus providing insight into human infertility in males due to similar problems with meiosis.

Meiosis, the cell division process giving rise to sperm and eggs, involves several steps, one of which is the formation of a large protein structure called the synaptonemal complex.

Like a bridge, the complex holds chromosome pairs in place enabling necessary genetic exchanges to occur that are essential for the chromosomes to then correctly separate into sperm and eggs.

“A significant contributor to infertility is defects in meiosis,” said Billmyre. 

“To understand how chromosomes separate into reproductive cells correctly, we are really interested in what happens right before that when the synaptonemal complex forms between them.”

Previous studies have examined many proteins comprising the synaptonemal complex, how they interact with each other, and have identified various mutations linked to male infertility. 

The protein the researchers investigated in this study forms the lattices of the proverbial bridge, which has a section found in humans, mice, and most other vertebrates suggesting it is critical for assembly. Modelling different mutations in a potentially crucial region in the human protein enabled the team to predict which of these might disrupt protein function.

The authors used a precise gene editing technique to make mutations in one key synaptonemal complex protein in mice, which allowed the researchers, for the first time, to test the function of key regions of the protein in live animals. Just a single mutation, predicted from the modelling experiments, was verified as the culprit of infertility in mice.

“We’re talking about pinpoint surgery here,” said Hawley. 

“We focused on a tiny little region of one protein in this gigantic structure that we were pretty sure could be a significant cause of infertility.”

Mice have long been used as models for human diseases. From the modelling experiments using human protein sequences, along with the high conservation of this protein structure across species, the precise molecule that caused infertility in mice likely functions the same way in humans.

“What is really exciting to me is that our research can help us understand this really basic process that is necessary for life,” said Billmyre.

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