Research ArticleHuman Genetics

A Common Mutation in the Defensin DEFB126 Causes Impaired Sperm Function and Subfertility

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Science Translational Medicine  20 Jul 2011:
Vol. 3, Issue 92, pp. 92ra65
DOI: 10.1126/scitranslmed.3002289

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Defensin-Deficient Sperm Get Stuck

Like Robert Burns’ best laid schemes of mice and men, the joining of egg and sperm “gang aft agley” (transl., often go awry)—and it’s no wonder, considering the many molecular events that must be correctly executed for successful fertilization. The current clinical tests still fail to explain infertility in almost one-fifth of infertile couples. Now, Tollner et al. pinpoint one more critical cog in this vital process: Men who carry a genetic variant of a certain sperm surface protein are less fertile than normal. This common but life-altering deviation likely accounts for some of the currently unexplained cases of infertility.

β-Defensin is a protein made in the paired coils of the epididymis, which carries sperm from testes. This defensin is secreted as the sperm travels by and is integrated into the glycocalyx, a protein-sugar coating on the sperm surface. Surface-hugging β-defensins protect sperm from immune attack and help them to penetrate the cervical mucus in the female. While cloning the human version of this defensin, the authors found a mutated variant that was surprisingly prevalent; about 20% of the European, Chinese, and Japanese men that the authors examined carried the variation on both chromosomes (del/del). Although they did not uniformly display deficiencies usually associated with infertility (such as inadequate semen volume and low sperm motility), sperm from del/del men did show lower lectin binding relative to controls; this measure was shown to be a marker for sperm-associated O-linked oligosaccharides that cannot attach to the mutated defensin. The del/del sperm were poor penetrators of hyaluronic acid, an in vitro surrogate for cervical mucus. But did the presence of the defensin variant actually cause lower fertility? In a group of 509 newly married Chinese couples, the authors showed that it did. Wives of men with the del/del genotype were only 60% as likely to get pregnant as were women who mated with men who carried wild-type or wt/del genotypes, and the time from enrollment in the study to the live birth of a child was 2 months longer in the former group.

The impaired fertility among carriers of this deletion might imply that these individuals are headed for extinction, but their prevalence in the population indicates otherwise. How can this be? The authors speculate that carriers of a single copy of the mutated defensin may have an as yet undefined survival advantage over wild-type carriers, an evolutionary situation known as balancing selection. Whatever the reason for variation persistence, our new understanding of β-defensin will enable better appreciation of human fertility and help to keep our reproductive plans on track.


  • Citation: 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).

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