Alterations in the steroid hormone receptor co-chaperone FKBPL are associated with male infertility: a case-control study.

BACKGROUND: Male infertility is a common cause of reproductive failure in humans.In mice, targeted deletions of the genes coding for FKBP6 or FKBP52, members ofthe FK506 binding protein family, can result in male infertility. In the case of FKBP52, this reflects an important role in potentiating Androgen Receptor (AR)signalling in the prostate and accessory glands, but not the testis. In infertilemen, no mutations of FKBP52 or FKBP6 have been found so far, but the gene forFKBP-like (FKBPL) maps to chromosome 6p21.3, an area linked to azoospermia in agroup of Japanese patients.METHODS: To determine whether mutations in FKBPL could contribute to theazoospermic phenotype, we examined expression in mouse and human tissues by RNAarray blot, RT-PCR and immunohistochemistry and sequenced the complete gene from two azoospermic patient cohorts and matching control groups. FKBPL-AR interactionwas assayed using reporter constructs in vitro.RESULTS: FKBPL is strongly expressed in mouse testis, with expression upregulatedat puberty. The protein is expressed in human testis in a pattern similar toFKBP52 and also enhanced AR transcriptional activity in reporter assays. Weexamined sixty patients from the Japanese patient group and found oneinactivating mutation and one coding change, as well as a number of non-codingchanges, all absent in fifty-six controls. A second, Irish patient cohort ofthirty showed another two coding changes not present in thirty proven fertilecontrols.CONCLUSIONS: Our results describe the first alterations in the gene for FKBPL in azoospermic patients and indicate a potential role in AR-mediated signalling inthe testis.