TollnerVenners ms & figs-1.pdf (853.77 kB)
A Common Mutation in the Defensin DEFB126 Causes Impaired Sperm Function and Subfertility
journal contribution
posted on 2012-10-24, 09:21 authored by Theodore L. Tollner, Scott A. Venners, Edward J. Hollox, Ashley I. Yudin, Xue Liu, Genfu Tang, Houxun Xing, Robert J. Kays, Tsang Lau, James W. Overstreet, Xiping Xu, Charles L. Bevins, Gary N. CherrA glycosylated polypeptide, β-defensin 126 (DEFB126), derived from the epididymis and adsorbed onto the sperm surface, has been implicated in immunoprotection and efficient movement of sperm in mucosal fluids of the female reproductive tract. Here, we report a sequence variant in DEFB126 that has a two-nucleotide deletion in the open reading frame, which generates an abnormal mRNA. The allele frequency of this variant sequence was high in both a European (0.47) and a Chinese (0.45) population cohort. Binding of the Agaricus bisporus lectin to the sperm surface glycocalyx was significantly lower in men with the homozygous variant (del/del) genotype than in those with either a del/wt or a wt/wt genotype, suggesting an altered sperm glycocalyx with fewer O-linked oligosaccharides in del/del men. Moreover, sperm from del/del carriers exhibited an 84% reduction in the rate of penetration of a hyaluronic acid gel, a surrogate for cervical mucus, compared to the other genotypes. This reduction in sperm performance in hyaluronic acid gels was not a result of decreased progressive motility (average curvilinear velocity) or morphological deficits. Nevertheless, DEFB126 genotype and lectin binding were correlated with sperm performance in the penetration assays. In a prospective cohort study of newly married couples who were trying to conceive by natural means, couples were less likely to become pregnant and took longer to achieve a live birth if the male partner was homozygous for the variant sequence. 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.
History
Citation
Science Translational Medicine, 2011, 3 (92), p. 92ra65Version
- AM (Accepted Manuscript)
Published in
Science Translational Medicineissn
1946-6234eissn
1946-6242Copyright date
2011Available date
2012-10-24Publisher DOI
Language
engAdministrator link
Usage metrics
Categories
Keywords
AdultAmino Acid SequenceBase SequenceCohort StudiesEpididymal Secretory ProteinsFemaleGelsGene Expression RegulationGene FrequencyGenotypeGlycosylationHumansHyaluronic AcidInfertilityMaleLectinsMolecular Sequence DataMutationOdds RatioPolymorphismSingle NucleotidePregnancyRNAMessengerSequence AlignmentSpermatozoaTissue DonorsYoung Adult
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC