UC DAVIS (US) — Sperm that lack a special protein coating have trouble reaching the egg. The discovery could open up new ways to screen and treat couples for infertility.
The research, reported this week in the journal Science Translational Medicine, suggests that a genetic mutation may be to blame—and may explain a significant proportion of male infertility worldwide.
The protein DEFB126 acts as a “Klingon cloaking device,” allowing sperm to swim through mucus and avoid the immune system in order to reach the egg, says Gary Cherr, co-senior author of the study and a professor of medical microbiology and immunology at the University of California, Davis.
Normal human sperm are seen above. Green dots show the presence of a sugary molecule that allows the sperm to swim through cervical mucus. Below are sperm from a donor with a defective gene for the coating protein. These sperm look normal and can swim, but have difficulty penetrating mucus. (Credit: UC Davis)
But the researchers found that many men carry a defective gene for DEFB126. A survey of samples from the U.S., United Kingdom and China showed that as many as a quarter of men worldwide carry two copies of the defective gene—which may significantly affect their fertility.
Infertility affects 10 to 15 percent of the US population, says John Gould, associate professor of urology at UC Davis, who was not involved in the research. About half of those cases involve problems with male fertility.
One of the mysteries of human fertility is that sperm quality and quantity seem to have little do with whether or not a man is fertile, says Ted Tollner, first author of the paper, who carried out the work as a postdoctoral scholar with Cherr. Tollner is now an adjunct assistant professor of obstetrics and gynecology at UC Davis.
“In 70 percent of men, you can’t predict their fertility on the basis of sperm count and routine assessment of sperm quality,” Cherr says. Studies like this may give us opportunities to explain these cases, adds Gould.
If the discovery were successfully developed into a test, it could be used to send couples directly to treatment with intracytoplasmic sperm injection or ICSI, in which eggs are removed from the woman and injected directly with sperm, avoiding an expensive workup to exclude other causes, Gould says.
Tollner and Cherr were looking for ways to make contraceptive vaccines when they started looking at DEFB126. The protein belongs to a class of molecules called defensins, natural germ-killers found on mucosal surfaces. DEFB126 is produced in the epididymis, the structure where sperm are stored after they are produced in the testes, and deposited onto sperm in the epididymis to form a thick coat.
They were trying to make antibodies to the human protein, without much success. So they enlisted the help of Bevins, an expert on defensins. Bevins’ lab made a recombinant copy of the human DEFB126 gene, with the aim of generating a purified protein that Tollner and Cherr could use to create antibodies.
On their first attempt, they found the gene had a mutation that prevented it from making a protein. But when they used sperm from a different donor, they were able to make the normal protein.
“If we hadn’t seen this in the first clone, we would be confused to this day,” Bevins says.
Sperm from men with the defective DEFB126 genes look normal under a microscope and swim around like normal sperm. But they are far less able to swim through an artificial gel made to resemble human cervical mucus.
When the normal protein is added to the sperm, they recover their normal abilities, the team found.
Working with an international team of researchers, the UC Davis group was able to look at the frequency of the gene in DNA samples from people in the US, UK, China, Japan and Africa. They found that worldwide, about half of all men carry one defective copy; a quarter have two defective copies and therefore make sperm that are poor at swimming through mucus.
Another team led by Scott Venners at Simon Fraser University was able to look at the effect of the mutation on a group of couples trying to conceive. They found a statistically significant decrease in the number of pregnancies in couples where the man carried two copies of the defective DEFB126 gene.
Why should a mutation that affects fertility be so astonishingly common? It may be that heterozygotes—men with one normal and one defective gene, but normal fertility—are advantaged in some way, Tollner explains.
Compared to sperm from monkeys and other mammals, Tollner says human sperm are typically poor quality, slow-swimming, and with a high rate of defective cells. It’s possible that because humans, unlike most mammals, breed in long-term monogamous relationships, sperm quality just does not matter very much, Cherr adds.
However, some researchers believe that, for reasons unknown, human male fertility has been falling worldwide in recent decades. That decline might be unmasking the problems associated with the defective DEFB126 gene.
Cherr says that they hope next to work with a major infertility program in the US to further explore the role of the mutation.
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