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”.
By surveying sperm samples from men in the US, UK and China, they found that as many as a quarter of men worldwide carry two copies of the defective DEFB126 variant and concluded this could significantly affect their fertility.
When you look at sperm from men with the defective variants under the microscope they look like normal sperm and swim around like normal sperm, the researchers said in a statement.
But, when they tested the sperms’ ability to swim through hyaluronic acid gel, an artificial gel made to resemble human cervical mucus, they found that sperm from carriers of two defective variants “exhibited an 84% reduction in the rate of penetration …compared to the other genotypes”.
And when they added normal beta-defensin 126 protein to the defective sperm, they recovered their normal abilities.
The researchers hope their discovery leads to the development of a test that could be used to send couples directly for treatment with “intracytoplasmic sperm injection” or ICSI, a procedure that removes the woman’s eggs and injects them directly with sperm outside of her body. This could save a lot of time, money and anguish with trying to find the cause of infertility via other procedures.
In another phase of the study that took place at Anhui Medical University in Anhui, China, the researchers carried out a prospective cohort study of newly married couples who were trying to conceive by natural means, and found that they were less likely to become pregnant and took longer to achieve a live birth if the male partner carried two copies of the defective DEFB126 gene.
The researchers concluded that:
“This common sequence variation in DEFB126, and its apparent effect of impaired reproductive function, will allow a better understanding, clinical evaluation, and possibly treatment of human infertility.”
But why should a mutation that affects fertility be so common?
Lead author of the study, Dr Ted Tollner, is an adjunct assistant professor in the UC Davis Department of Obstetrics and Gynecology. He worked on the study as a postdoctoral scholar with Cherr.
“It may be that heterozygotes — men with one normal and one defective gene, but normal fertility — are advantaged in some way,” said Tollner.
He explained that the quality of human sperm is typically quite poor compared to sperm from monkey and other mammals. It swims slowly and has a high rate of defective cells.
Cherr said perhaps because humans tend to have long-term, monogamous relationships, sperm quality is just not that important.
But some researchers say that human male fertility has been falling worldwide in recent decades, and we don’t know why.
Cherr said the next step is to do some research within a major infertility project in the US and find out more about the role of the defective DEFB126 gene.
Funds from the National Science Foundation and the National Institutes of Health helped pay for the study.
“A Common Mutation in the Defensin DEFB126 Causes Impaired Sperm Function and Subfertility.”
Theodore L. Tollner, Scott A. Venners, Edward J. Hollox, Ashley I. Yudin, Xue Liu, Genfu Tang, and others.
Sci Transl Med, Vol. 3, Issue 92, p. 92ra65; 20 July 2011; DOI: 10.1126/scitranslmed.3002289
Additional source: UC Davis.
Written by: Catharine Paddock, PhD