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

Male infertility is a common cause of reproductive failure in humans. In mice, targeted deletions of the genes coding for FKBP6 or FKBP52, members of the FK506 binding protein family, can result in male infertility. In the case of FKBP52, this reflects an important role in potentiating Androgen Rece...

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Published in:	Reproductive biology and endocrinology Vol. 8; no. 1; p. 22
Main Authors:	Sunnotel, Olaf, Hiripi, Laszlo, Lagan, Kevin, McDaid, Jennifer R, De León, Johanny M, Miyagawa, Yasushi, Crowe, Hannah, Kaluskar, Soniya, Ward, Michael, Scullion, Catherine, Campbell, Alan, Downes, C S, Hirst, David, Barton, David, Mocanu, Edgar, Tsujimura, Akira, Cox, Marc B, Robson, Tracy, Walsh, Colum P
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 08-03-2010 BioMed Central BMC
Subjects:	Amino Acid Sequence Animals Case-Control Studies Cohort Studies Genes Genetic aspects Genetic Linkage Genetic Predisposition to Disease Hormone receptors Humans Immunophilins - genetics Infertility Infertility, Male Infertility, Male - genetics Male Medical research Mice Molecular chaperones Molecular Sequence Data Mutation Mutation - physiology Physiological aspects Proteins Risk factors Sequence Homology, Amino Acid Steroid hormones Tissue Array Analysis United Kingdom Ireland
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Summary:	Male infertility is a common cause of reproductive failure in humans. In mice, targeted deletions of the genes coding for FKBP6 or FKBP52, members of the 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 infertile men, no mutations of FKBP52 or FKBP6 have been found so far, but the gene for FKBP-like (FKBPL) maps to chromosome 6p21.3, an area linked to azoospermia in a group of Japanese patients. To determine whether mutations in FKBPL could contribute to the azoospermic phenotype, we examined expression in mouse and human tissues by RNA array blot, RT-PCR and immunohistochemistry and sequenced the complete gene from two azoospermic patient cohorts and matching control groups. FKBPL-AR interaction was assayed using reporter constructs in vitro. FKBPL is strongly expressed in mouse testis, with expression upregulated at puberty. The protein is expressed in human testis in a pattern similar to FKBP52 and also enhanced AR transcriptional activity in reporter assays. We examined sixty patients from the Japanese patient group and found one inactivating mutation and one coding change, as well as a number of non-coding changes, all absent in fifty-six controls. A second, Irish patient cohort of thirty showed another two coding changes not present in thirty proven fertile controls. Our results describe the first alterations in the gene for FKBPL in azoospermic patients and indicate a potential role in AR-mediated signalling in the testis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1477-7827 1477-7827
DOI:	10.1186/1477-7827-8-22