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Scientists Uncover a New, Genetic Cause of Male Infertility---And It Appears to be Widespread

By Veronique Greenwood
Jul 21, 2011 6:38 PMNov 20, 2019 2:39 AM


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What's the News: What if the egg is fine and the sperm is dandy, but you still can't seem to have a baby? Couples who are having trouble conceiving can testify to the frustration of learning that there's no clear reason for their infertility. Now, however, scientists have found a genetic mutation that makes outwardly normal sperm much less fertile

, potentially explaining many such cases and suggesting new routes to conception. What's the Context:

  • Infertility is defined as failure to conceive after a year of unprotected sex. About 10-15% of couples run into this problem.

  • Some cases of infertility are fairly easily explained: there may be a shortage of sperm, or they may be unable to swim far enough to make it to the egg. The eggs in turn may be malformed, or the womb may have conditions that make implantation of the fertilized egg difficult. But in about 20% of infertile couples, it's not clear what is impeding the process.

  • When treating infertility, knowing the source of the problem is a big help. For instance, if the problem is the number of sperm, one option is concentrating sperm into a single sample and trying with that. But if the problem is with the womb, then in vitro fertilization, where eggs are fertilized by sperm in a Petri dish and then implanted, might be a better option.

How the Heck:

  • The scientists investigated a mutant variant of the gene for DEFB126, a protein that's found on the membrane of sperm cells. Due to a mix-up with a genetic stop sign, this variant produces a protein that's longer than the normal version.

  • Humans have two copies of each gene, one from each parent. When both of a man's copies of a gene had the mutation, the cells' quality control mechanisms seemed to destroy most of the proteins, and sperm had correspondingly fewer of them on their surfaces, though they seemed otherwise perfectly healthy. But when the scientists tried to get them to swim through a laboratory version of cervical mucus, nearly all of them stalled and got stuck. The more protein a sperm had, the more likely it was to swim through.

  • To see if this gene variant was related to infertility in real life, the scientists then tracked about 500 newlywed couples for two years. They found that couples in which the man had the mutation in both genes, the woman was significantly less likely to get pregnant. While this relationship will need to be backed up by more studies, it's intriguing.

  • No current test for male infertility, the researchers point out, would alert men of this problem.

The Future Holds:

  • How exactly would this variant cause infertility? In monkeys, the normal protein is known to help sperm get through cervical mucus, keep sperm safe from the female's immune system, and aid in sperm's attachment to the fallopian tubes. If having this mutant version impedes any one of those processes, it could contribute to a couple's inability to get pregnant.

  • Figuring out what is going on could suggest treatments for infertility caused this way---for instance, sperm could be supplied with normal versions of the protein, or couples, once alerted to the problem, could go straight to in vitro fertilization instead of trying other methods that rely on the robustness of sperm.

  • What's incredibly strange about this discovery, though, is that this variant is common. So common, in fact, that about 20% of the population seems to have it, judging from the scientists' analysis of genetic databases. That seems to indicate that being heterozygous for the variant---having one normal gene and one mutant one, as many men do---might have some evolutionary benefit, like resistance to disease, that, on the level of the population, counterbalances the apparent infertility caused by having two copies of it. At this point any such explanations are purely speculative, but for geneticists, this promises to be a fascinating knot to untangle.

Reference: T. L. Tollner, S. A. Venners, E. J. Hollox, A. I. Yudin, X. Liu, G. Tang, H. Xing, R. J. Kays, T. Lau, J. W. Overstreet, X. Xu, C. L. Bevins, G. N. Cherr, A common mutation in the defensin DEFB126 causes impaired sperm function and subfertility.

Sci. Transl. Med. 3, 92ra65 (2011).

Image credit: Santa Rosa OLD SKOOL / flickr

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