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

Reproductive Biology and Endocrinology

Research

Johanny M De León¹  Marc B Cox¹  CS Downes²  Akira Tsujimura³  Yasushi Miyagawa³  Edgar Mocanu⁴  David Barton⁵  David Hirst⁶  Tracy Robson⁶  Alan Campbell⁷  Jennifer R McDaid⁷  Soniya Kaluskar⁷  Colum P Walsh⁷  Michael Ward⁷  Kevin Lagan⁷  Catherine Scullion⁷  Olaf Sunnotel⁷  Laszlo Hiripi⁷  Hannah Crowe⁷ 

[1] Border Biomedical Research Center, University of Texas at El Paso, 79902, TX, USA;Cancer and Ageing Research Group, School of Biomedical Sciences, University of Ulster, BT52 1SA,, Coleraine, UK;Dept of Urology, University of Osaka Graduate School of Medicine, Suita, Osaka, Japan;Human Assisted Reproduction Ireland, Rotunda Hospital, Dublin 1,, Ireland;National Centre for Medical Genetics Our Lady's Children's Hospital, Crumlin, Dublin, Ireland;School of Pharmacy, Queen's University, BT9 7BL, Belfast, UK;Transcriptional Regulation and Epigenetics, School of Biomedical Sciences, University of Ulster, BT52 1SA, Coleraine, UK;

关键词: Androgen Receptor;    Sertoli Cell;    Leydig Cell;    Azoospermia;    Androgen Receptor Activity;   

DOI  :  10.1186/1477-7827-8-22

 received in 2009-11-16, accepted in 2010-03-08,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundMale 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.MethodsTo 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.ResultsFKBPL 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.ConclusionsOur 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.

【 授权许可】

Unknown   
© Sunnotel et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.