Mutations in the chromosome pairing gene FKBP6 are not a common cause of non-obstructive azoospermia

Abstract

Although it is generally thought that spermatogenic failure has a genetic background, to date only a limited percentage of men with non-obstructive azoospermia (NOA) are diagnosed with a genetic defect. The only common and well-established genetic causes of NOA in humans are numerical and structural chromosomal abnormalities and Y-chromosome deletions. In addition, some infrequent mutations have been identified in the ubiquitin-specific protease 9, Y-linked (USP9Y) and the synaptonemal complex protein 3 (SYCP3) gene that cause azoospermia. FK506-binding protein 6 (Fkbp6) is a newly discovered component of the synaptonemal complex (SC), which is essential for proper chromosome pairing and meiotic division. A null mutation of the Fkbp6 gene causes azoospermia in mice as well as in rats. We tested the hypothesis whether mutations in this gene can also cause azoospermia in humans. We performed a mutation screen in 51 men with NOA through direct sequencing methods. No homozygous mutations were identified. Two heterozygous mutations (T173T and R183C) were identified, which are likely to disrupt FKBP6 protein function. However, both mutations were also found in a group of 218 normospermic controls indicating that one FKBP6 allele appears to be sufficient for normal spermatogenesis. In conclusion, our results suggest that genetic defects in FKBP6 can be excluded as a common cause of azoospermia in humans.