Male Infertility Tied To Common Gene Mutation That Lets Sperm Get Zapped By Female Immune System

A common gene mutation that causes sperm to lose its protective protein coat so it falls prey to the female immune system on its journey to the egg, may be the main reason for infertility in men worldwide, writes an international team of researchers in a paper published in the journal Science Translational Medicine this week. The researchers hope their discovery will help to find new ways to treat infertile couples.

Infertility affects between 10 and 15% of the US population, and in about half of these cases, the problem is male fertility.

Co-senior author of the paper, Dr Gary Cherr, a professor at the University of California Davis' Bodega Marine Laboratory and Center for Health and Environment, told the press that:

"In 70 percent of men, you can't predict their fertility on the basis of sperm count and routine assessment of sperm quality."

He and his colleagues, including co-senior author Dr Charles Bevins, professor in the Department of Medical Microbiology and Immunology at UC Davis, hope their findings will help to explain why.

The researchers were investigating defensins, natural germ-killer proteins found on mucosal surfaces, in a search for ways to make contraceptive vaccines, when they came across one called beta-defensin 126 and started looking more closely at its properties.

Beta-defensin 126, a "glycosylated polypeptide" protein coded by the gene known as DEFB126, behaves like a cloaking device that allows the sperm to swim efficiently through the mucus in the female's reproductive tract and reach the egg without being detected by her immune system.

The protein is synthesized in the male's epididymis, the coiled ducts that store, mature and transport sperm cells on their way from the testis where they are made, to the vas deferens, from whence they are delivered to the urethra prior to ejaculation. It is while they are in the epididymis, "readying" themselves for the ejaculatory "launch", that the sperm cells receive their thick protective coating of beta-defensin 126.

The researchers came upon their discovery almost by chance, as often happens in science. They were trying to obtain purified beta-defensin 126 to make some antibodies to the protein. To do this they had to make a recombinant copy of the DEFB126 gene, but in their first attempt they found the gene had a mutation that prevented it from making the protein.

But when they used sperm from a different donor, they were able to make the protein.

Bevins said:

"If we hadn't seen this in the first clone, we would be confused to this day."

And what Cherr, Bevins and colleagues found was that many men carry a defective DEFB126 gene. They describe their finding as a "sequence variant in DEFB126 that has a two-nucleotide deletion in the open reading frame, which generates an abnormal mRNA".