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Article: Oligospermic infertility associated with an androgen receptor mutation that disrupts interdomain and coactivator (TIF2) interactions

TitleOligospermic infertility associated with an androgen receptor mutation that disrupts interdomain and coactivator (TIF2) interactions
Authors
Issue Date1999
PublisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org
Citation
Journal 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.
Persistent Identifierhttp://hdl.handle.net/10722/43606
ISSN
2014 Impact Factor: 13.215
2013 SCImago Journal Rankings: 9.511
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorGhadessy, FJen_HK
dc.contributor.authorLim, Jen_HK
dc.contributor.authorAbdullah, AAen_HK
dc.contributor.authorPanet-Raymond, Ven_HK
dc.contributor.authorChoo, CKen_HK
dc.contributor.authorLumbroso, Ren_HK
dc.contributor.authorTut, TGen_HK
dc.contributor.authorGottlieh, Ben_HK
dc.contributor.authorPinsky, Len_HK
dc.contributor.authorTrifiro, MAen_HK
dc.contributor.authorYong, ELen_HK
dc.date.accessioned2007-03-23T04:50:10Z-
dc.date.available2007-03-23T04:50:10Z-
dc.date.issued1999en_HK
dc.identifier.citationJournal of Clinical Investigation, 1999, v. 103 n. 11, p. 1517-1525en_HK
dc.identifier.issn0021-9738en_HK
dc.identifier.urihttp://hdl.handle.net/10722/43606-
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.en_HK
dc.format.extent331188 bytes-
dc.format.extent25088 bytes-
dc.format.mimetypeapplication/pdf-
dc.format.mimetypeapplication/msword-
dc.languageengen_HK
dc.publisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.orgen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshAndrogens - metabolismen_HK
dc.subject.meshBinding sitesen_HK
dc.subject.meshMutation, missenseen_HK
dc.subject.meshPoint mutationen_HK
dc.subject.meshTranscription factors - metabolismen_HK
dc.titleOligospermic infertility associated with an androgen receptor mutation that disrupts interdomain and coactivator (TIF2) interactionsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0021-9738&volume=103&issue=11&spage=1517&epage=1525&date=1999&atitle=Oligospermic+infertility+associated+with+an+androgen+receptor+mutation+that+disrupts+interdomain+and+coactivator+(TIF2)+interactionsen_HK
dc.description.naturepublished_or_final_versionen_HK
dc.identifier.pmid10359561en_HK
dc.identifier.pmcidPMC408364-
dc.identifier.scopuseid_2-s2.0-0032727702-
dc.identifier.hkuros41566-
dc.identifier.isiWOS:000083468100007-

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