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Article: Oligospermic infertility associated with an androgen receptor mutation that disrupts interdomain and coactivator (TIF2) interactions
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TitleOligospermic infertility associated with an androgen receptor mutation that disrupts interdomain and coactivator (TIF2) interactions
 
AuthorsGhadessy, FJ1
Lim, J1
Abdullah, AA
Panet-Raymond, V3
Choo, CK1
Lumbroso, R3
Tut, TG1
Gottlieh, B
Pinsky, L3
Trifiro, MA3
Yong, EL1 2
 
Issue Date1999
 
PublisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org
 
CitationJournal of Clinical Investigation, 1999, v. 103 n. 11, p. 1517-1525 [How to Cite?]
 
AbstractStructural changes in the androgen receptor (AR) are one of the causes of defective spermatogenesis. We screened the AR gene of 173 infertile men with impaired spermatogenesis and identified 3 of them, unrelated, who each had a single adenineguanine transition that changed codon 886 in exon 8 from methionine to valine. This mutation was significantly associated with the severely oligospermic phenotype and was not detected in 400 control AR alleles. Despite the location of this substitution in the ligand-binding domain (LBD) of the AR, neither the genital skin fibroblasts of the subjects nor transfected cell types expressing the mutant receptor had any androgen-binding abnormality. However, the mutant receptor had a consistently (approximately 50%) reduced capacity to transactivate each of 2 different androgen-inducible reporter genes in 3 different cell lines. Deficient transactivation correlated with reduced binding of mutant AR complexes to androgen response elements. Coexpression of AR domain fragments in mammalian and yeast two-hybrid studies suggests that the mutation disrupts interactions of the LBD with another LBD, with the NH2-terminal transactivation domain, and with the transcriptional intermediary factor TIF2. These data suggest that a functional element centered around M886 has a role, not for ligand binding, but for interdomain and coactivator interactions culminating in the formation of a normal transcription complex.
 
ISSN0021-9738
2013 Impact Factor: 13.765
2013 SCImago Journal Rankings: 9.511
 
PubMed Central IDPMC408364
 
ISI Accession Number IDWOS:000083468100007
 
DC FieldValue
dc.contributor.authorGhadessy, FJ
 
dc.contributor.authorLim, J
 
dc.contributor.authorAbdullah, AA
 
dc.contributor.authorPanet-Raymond, V
 
dc.contributor.authorChoo, CK
 
dc.contributor.authorLumbroso, R
 
dc.contributor.authorTut, TG
 
dc.contributor.authorGottlieh, B
 
dc.contributor.authorPinsky, L
 
dc.contributor.authorTrifiro, MA
 
dc.contributor.authorYong, EL
 
dc.date.accessioned2007-03-23T04:50:10Z
 
dc.date.available2007-03-23T04:50:10Z
 
dc.date.issued1999
 
dc.description.abstractStructural changes in the androgen receptor (AR) are one of the causes of defective spermatogenesis. We screened the AR gene of 173 infertile men with impaired spermatogenesis and identified 3 of them, unrelated, who each had a single adenineguanine transition that changed codon 886 in exon 8 from methionine to valine. This mutation was significantly associated with the severely oligospermic phenotype and was not detected in 400 control AR alleles. Despite the location of this substitution in the ligand-binding domain (LBD) of the AR, neither the genital skin fibroblasts of the subjects nor transfected cell types expressing the mutant receptor had any androgen-binding abnormality. However, the mutant receptor had a consistently (approximately 50%) reduced capacity to transactivate each of 2 different androgen-inducible reporter genes in 3 different cell lines. Deficient transactivation correlated with reduced binding of mutant AR complexes to androgen response elements. Coexpression of AR domain fragments in mammalian and yeast two-hybrid studies suggests that the mutation disrupts interactions of the LBD with another LBD, with the NH2-terminal transactivation domain, and with the transcriptional intermediary factor TIF2. These data suggest that a functional element centered around M886 has a role, not for ligand binding, but for interdomain and coactivator interactions culminating in the formation of a normal transcription complex.
 
dc.description.naturepublished_or_final_version
 
dc.format.extent331188 bytes
 
dc.format.extent25088 bytes
 
dc.format.mimetypeapplication/pdf
 
dc.format.mimetypeapplication/msword
 
dc.identifier.citationJournal of Clinical Investigation, 1999, v. 103 n. 11, p. 1517-1525 [How to Cite?]
 
dc.identifier.hkuros41566
 
dc.identifier.isiWOS:000083468100007
 
dc.identifier.issn0021-9738
2013 Impact Factor: 13.765
2013 SCImago Journal Rankings: 9.511
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC408364
 
dc.identifier.pmid10359561
 
dc.identifier.scopuseid_2-s2.0-0032727702
 
dc.identifier.urihttp://hdl.handle.net/10722/43606
 
dc.languageeng
 
dc.publisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
dc.subject.meshAndrogens - metabolism
 
dc.subject.meshBinding sites
 
dc.subject.meshMutation, missense
 
dc.subject.meshPoint mutation
 
dc.subject.meshTranscription factors - metabolism
 
dc.titleOligospermic infertility associated with an androgen receptor mutation that disrupts interdomain and coactivator (TIF2) interactions
 
dc.typeArticle
 
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<contributor.author>Panet-Raymond, V</contributor.author>
<contributor.author>Choo, CK</contributor.author>
<contributor.author>Lumbroso, R</contributor.author>
<contributor.author>Tut, TG</contributor.author>
<contributor.author>Gottlieh, B</contributor.author>
<contributor.author>Pinsky, L</contributor.author>
<contributor.author>Trifiro, MA</contributor.author>
<contributor.author>Yong, EL</contributor.author>
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<description.abstract>Structural changes in the androgen receptor (AR) are one of the causes of defective spermatogenesis. We screened the AR gene of 173 infertile men with impaired spermatogenesis and identified 3 of them, unrelated, who each had a single adenineguanine transition that changed codon 886 in exon 8 from methionine to valine. This mutation was significantly associated with the severely oligospermic phenotype and was not detected in 400 control AR alleles. Despite the location of this substitution in the ligand-binding domain (LBD) of the AR, neither the genital skin fibroblasts of the subjects nor transfected cell types expressing the mutant receptor had any androgen-binding abnormality. However, the mutant receptor had a consistently (approximately 50%) reduced capacity to transactivate each of 2 different androgen-inducible reporter genes in 3 different cell lines. Deficient transactivation correlated with reduced binding of mutant AR complexes to androgen response elements. Coexpression of AR domain fragments in mammalian and yeast two-hybrid studies suggests that the mutation disrupts interactions of the LBD with another LBD, with the NH2-terminal transactivation domain, and with the transcriptional intermediary factor TIF2. These data suggest that a functional element centered around M886 has a role, not for ligand binding, but for interdomain and coactivator interactions culminating in the formation of a normal transcription complex.</description.abstract>
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Author Affiliations
  1. National University of Singapore
  2. National University Hospital, Singapore
  3. McGill University