Sequence alterations in the YBX2 gene are associated with male factor infertility

Objective To investigate YBX2 gene alterations in men with severe defects in spermatogenesis, including azoospermia or severe oligozoospermia, and protamine deregulation. MSY2 has been identified as a central component in the regulation of spermatogenesis in mice, but the potential role of its human orthologue, YBX2 or “Contrin,” in human infertility is not known. Design A prospective cohort study. Setting University infertility clinic and associated research laboratory. Patient(s) A total of 288 men were evaluated. Diagnoses were made of complete azoospermia, severe oligozoospermia, and protamine deregulation, or men were of known paternity. Intervention(s) Deoxyribonucleic acid (from peripheral blood) and semen samples were collected and analyzed for gene mutations and semen parameters respectively. Main Outcome Measure(s) YBX2 gene alterations. Result(s) YBX2 sequence analysis revealed 15 polymorphic sites, of which seven polymorphisms were present at a statistically higher frequency in one or both of the patient populations than in controls. Of these seven, two resulted in an amino acid substitution in the highly conserved cold shock domain and one resulted in a highly significant synonymous change in exon 8 of infertile patients. The frequency of single nucleotide polymorphisms was significantly elevated in patients with infertility, particularly in men with abnormal protamine expression. Conclusion(s) These data indicate a significant association between gene alterations in the YBX2 gene and abnormal spermatogenesis in humans, including a potential role in altering protamine expression, and implicate YBX2 gene alterations as a potential cause of male factor infertility.