title: A common mutation in the defensin DEFB126 causes impaired sperm function and subfertility.
abstract: A 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.
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, University of California, Davis, CA 95817, USA.
authors.forename: Theodore L
authors.initials: TL
authors.lastname: Tollner
authors.forename: Scott A
authors.initials: SA
authors.lastname: Venners
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hollox
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Yudin
authors.forename: Xue
authors.initials: X
authors.lastname: Liu
authors.forename: Genfu
authors.initials: G
authors.lastname: Tang
authors.forename: Houxun
authors.initials: H
authors.lastname: Xing
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kays
authors.forename: Tsang
authors.initials: T
authors.lastname: Lau
authors.forename: James W
authors.initials: JW
authors.lastname: Overstreet
authors.forename: Xiping
authors.initials: X
authors.lastname: Xu
authors.forename: Charles L
authors.initials: CL
authors.lastname: Bevins
authors.forename: Gary N
authors.initials: GN
authors.lastname: Cherr
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D015331:Cohort Studies; D030501:Epididymal Secretory Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005782:Gels; D005786:Gene Expression Regulation; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006031:Glycosylation; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D007248:Infertility, Male / Q000235:genetics* / Q000503:physiopathology*; D037102:Lectins / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D013094:Spermatozoa / Q000473:pathology*; D014019:Tissue Donors; D055815:Young Adult; D023083:beta-Defensins
chemical_list: C041433:Agaricus lectins; C426184:DEFB126 protein, human; D030501:Epididymal Secretory Proteins; D005782:Gels; D037102:Lectins; D012333:RNA, Messenger; D023083:beta-Defensins; D006820:Hyaluronic Acid