A common mutation in the defensin DEFB126 causes impaired sperm function and subfertility

Area of Science:

• Reproductive biology
• Human genetics
• Spermatozoa function

Background:

• Beta-defensin 126 (DEFB126) is crucial for sperm immunoprotection and motility in the female reproductive tract.
• A specific DEFB126 sequence variant leads to abnormal mRNA and altered sperm surface characteristics.

Purpose of the Study:

• To investigate the functional consequences of a common DEFB126 sequence variant on sperm performance and male fertility.
• To determine the prevalence of this variant in different populations.

Main Methods:

• Genotyping of DEFB126 in European and Chinese cohorts.
• Assessing sperm glycocalyx using Agaricus bisporus lectin binding.
• Evaluating sperm penetration through hyaluronic acid gels.
• Prospective cohort study of couples trying to conceive.

Main Results:

• The DEFB126 variant (del/del genotype) was common (allele frequency ~0.46) in both populations.
• Homozygous variant men showed reduced lectin binding, indicating fewer O-linked oligosaccharides on sperm.
• Sperm from del/del men had an 84% lower penetration rate in hyaluronic acid gels.
• Male carriers of the homozygous variant had reduced pregnancy rates and longer time to live birth.

Conclusions:

• The common DEFB126 variant significantly impairs sperm function and is associated with reduced male fertility.
• This genetic variation provides a potential biomarker for evaluating male infertility.
• Understanding this variant may lead to new clinical evaluations and treatments for infertility.