Sperm Gene May Explain Some Male Infertility

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A mutation in a gene for a sperm-related protein found in 20% of men may be responsible for a significant proportion of unexplained male infertility, according to a new study.

About 15% of couples trying to conceive will not do so within a year, which is the definition of infertility used by the World Health Organization.  Among those couples, around half of the time the problem is related to the man and in 17% of male infertility cases, no cause can be identified.

Researchers studied the impact of the gene, called DEFB126, in 500 Chinese newlyweds attempting to start a family.  In couples where the man had two copies of the mutant version, the odds of childbirth in any given month were reduced by 30% and the average time to conception was delayed by two months compared to couples in which the male had only one or no copies of the aberrant gene.

“The probability that couples will be unable to conceive will increase significantly if men lack the normal gene for DEFB,” said Gary Cherr, professor of environmental toxicology at the University of California-Davis, the lead author of the study, speaking at a press conference to mark the publication in the journal Science Translational Medicine.

During development, sperm are coated with sugar, DEFB and other proteins as they travel through the twists of the epididymis in the testicles.  During fertilization, DEFB helps sperm pass through cervical mucus on the way to the egg. It may also play a role in helping sperm to evade the female immune system, which could otherwise mark them for destruction as foreign invaders.

The study found that sperm from men with the DEFB126 variant had an 84% decreased ability travel through a gel test that doctors use  to predict sperm’s capacity to travel in cervical mucus and lead to fertilization.

Although the study of conception was done with Chinese couples, researchers discovered the variant in one in five men in every population they examined, including Japanese, African, European and Californian men.

Genes are inherited in pairs, with one version coming from each parent.  While only 20% of men inherit mutant copies from both parents, around half of all men possess one mutant DEFB gene.

So why would something so potentially harmful to reproduction remain so common?  It’s possible that while having two copies of the gene is harmful, having one is helpful.  For example, there are genes that help to fight malaria:  if you get one copy of the mutant gene, you are less susceptible to that disease.  If you get two, however, you develop a painful blood disorder called sickle cell disease.

The same might be true of DEFB. “We don’t know what the selective advantage for [people with just one copy] might be,” said Dr. Charles Bevins, professor of medical microbiology and immunology at UC-Davis, another of the study’s authors, speculating that it could possibly help sperm swim better or otherwise improve their quality.

Those studies aren’t likely to yield easy answers, at least not in the near future. On other measures—like motility, sperm count and sperm shape— the semen quality of men with two copies of the mutant gene appears normal.  So understanding why maintain proper sperm function but fail in their most critical job—fertilizing eggs—might lead to better understanding of sperm quality.

Because the mutation only reduces fertility, in many situations, it might simply delay rather than prevent conception. But in cases where time is of the essence—for example, where the female partner is older and towards the end of her child-bearing years—testing for the gene could guide treatment.  If a man has the mutation, intrauterine insemination (IUI) might be an option:  with this technique, the sperm are introduced directly into the uterus so they don’t have to swim through the cervix.

Alternatively, in vitro fertilization using ICSI, in which the sperm is injected directly into the egg, could also be used.

The research also suggests that a technique to add the missing protein to the sperm could be helpful.  Researchers have already tried this approach with the sperm of nonhuman primates and it could potentially be applied as a vaginal gel before intercourse.

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