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

Olaf Sunnotel, Colum Walsh, Stephen Downes, Kevin Lagan

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.
LanguageEnglish
JournalReproductive Biology and Endocrinology
Volume8
Issue number22
DOIs
Publication statusPublished - 8 Mar 2010

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Steroid Receptors
Male Infertility
Case-Control Studies
Androgen Receptors
Hormones
Testis
Mutation
Tacrolimus Binding Proteins
Genes
Azoospermia
Gene Deletion
Puberty
Prostate
Chromosomes
Immunohistochemistry
Phenotype
Polymerase Chain Reaction
Control Groups
tacrolimus binding protein 4
Proteins

Keywords

  • steroird hormone mutations

Cite this

@article{f0e90771a49249b9938047cffc34cb66,
title = "Alterations in the steroid hormone receptor co-chaperone FKBPL are associated with male infertility: a case-control study.",
abstract = "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.",
keywords = "steroird hormone mutations",
author = "Olaf Sunnotel and Colum Walsh and Stephen Downes and Kevin Lagan",
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Alterations in the steroid hormone receptor co-chaperone FKBPL are associated with male infertility: a case-control study. / Sunnotel, Olaf; Walsh, Colum; Downes, Stephen; Lagan, Kevin.

In: Reproductive Biology and Endocrinology, Vol. 8, No. 22, 08.03.2010.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Alterations in the steroid hormone receptor co-chaperone FKBPL are associated with male infertility: a case-control study.

AU - Sunnotel, Olaf

AU - Walsh, Colum

AU - Downes, Stephen

AU - Lagan, Kevin

PY - 2010/3/8

Y1 - 2010/3/8

N2 - 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.

AB - 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.

KW - steroird hormone mutations

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DO - 10.1186/1477-7827-8-22

M3 - Article

VL - 8

JO - Reproductive Biology and Endocrinology

T2 - Reproductive Biology and Endocrinology

JF - Reproductive Biology and Endocrinology

SN - 1477-7827

IS - 22

ER -