title: Aberrant splicing of androgen receptor mRNA results in synthesis of a nonfunctional receptor protein in a patient with androgen insensitivity.
abstract: Androgen insensitivity is a disorder in which the correct androgen response in an androgen target cell is impaired. The clinical symptoms of this X chromosome-linked syndrome are presumed to be caused by mutations in the androgen receptor gene. We report a G----T mutation in the splice donor site of intron 4 of the androgen receptor gene of a 46,XY subject lacking detectable androgen binding to the receptor and with the complete form of androgen insensitivity. This point mutation completely abolishes normal RNA splicing at the exon 4/intron 4 boundary and results in the activation of a cryptic splice donor site in exon 4, which leads to the deletion of 123 nucleotides from the mRNA. Translation of the mutant mRNA results in an androgen receptor protein approximately 5 kDa smaller than the wild type. This mutated androgen receptor protein was unable to bind androgens and unable to activate transcription of an androgen-regulated reporter gene construct. This mutation in the human androgen receptor gene demonstrates the importance of an intact steroid-binding domain for proper androgen receptor functioning in vivo.
authors.affiliation: Department of Biochemistry II, Erasmus University, Rotterdam, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Ris-Stalpers
authors.forename: G G
authors.initials: GG
authors.lastname: Kuiper
authors.forename: P W
authors.initials: PW
authors.lastname: Faber
authors.forename: H U
authors.initials: HU
authors.lastname: Schweikert
authors.forename: H C
authors.initials: HC
authors.lastname: van Rooij
authors.forename: N D
authors.initials: ND
authors.lastname: Zegers
authors.forename: M B
authors.initials: MB
authors.lastname: Hodgins
authors.forename: H J
authors.initials: HJ
authors.lastname: Degenhart
authors.forename: J
authors.initials: J
authors.lastname: Trapman
authors.forename: A O
authors.initials: AO
authors.lastname: Brinkmann
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D005091:Exons; D005262:Feminization / Q000235:genetics* / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D007621:Karyotyping; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D015345:Oligonucleotide Probes; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics*; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics*; D012867:Skin / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D011944:Receptors, Androgen