Identification of two homozygous mutations, in the male reproductive tract specific beta-defensin 126/128 genes, potentially underlie a severe sperm dysfunction

Introduction: Idiopathic infertility affects 15% couples globally and recent evidence suggests genetic abnormalities are a causative factor in a significant number of cases. Hence, we conducted whole exome sequencing of men undergoing assisted conception to identify genetic lesions. The β-defensin 126 (DEFB126) and β-defensin 128 (DEFB128), are genes preferentially expressed in the epididymis, where these proteins may help protect the maturing sperm cells and play a vital role during sperm capacitation.

Materials and Methods: DNA extracted from the blood of 26 unrelated, sub-fertile men were sequenced using whole exome sequencing. Pathogenic rare variants were identified using bioinformatics analysis and validated using Sanger sequencing.

Results: A novel and rare homozygous pathogenic 1-bp frame-shift insertion causing a premature stop codon was identified in DEFB128 gene from one patient. Six patients showed a previously reported homozygous 2bp deletion, causing a frame-shift mutation in the DEFB126 gene (p.Pro106ArgfsTer?). All patients ascertained with the DEFB126/DEFB128 mutations were unable to naturally conceive and hence were sub-fertile.

Conclusions: The DEFB128 mutation (rs11396059), is rare and has not been associated with any disease to date. As the patient with the DEFB128 mutation has no other medical condition we predict that it is the cause of infertility. The DEFB126 mutation (rs140685149), is a common variant, and this homozygous variant in sub-fertile men has previously been implicated in facilitating sperm movement in the female reproductive tract. These results suggest that, β-defensin genes play a significant role in male reproduction.