title: Variable loss of functional activities of androgen receptor mutants in patients with androgen insensitivity syndrome.
abstract: Androgen receptor (AR) mutations in androgen insensitivity syndrome (AIS) are associated with a variety of clinical phenotypes. The aim of the present study was to compare the molecular properties and potential pathogenic nature of 8 novel and 3 recurrent AR variants with a broad variety of functional assays. Eleven AR variants (p.Cys177Gly, p.Arg609Met, p.Asp691del, p.Leu701Phe, p.Leu723Phe, p.Ser741Tyr, p.Ala766Ser, p.Arg775Leu, p.Phe814Cys, p.Lys913X, p.Ile915Thr) were analyzed for hormone binding, transcriptional activation, cofactor binding, translocation to the nucleus, nuclear dynamics, and structural conformation. Ligand-binding domain variants with low to intermediate transcriptional activation displayed aberrant Kd values for hormone binding and decreased nuclear translocation. Transcriptional activation data, FxxFF-like peptide binding and DNA binding correlated well for all variants, except for p.Arg609Met, p.Leu723Phe and p.Arg775Leu, which displayed a relatively higher peptide binding activity. Variants p.Cys177Gly, p.Asp691del, p.Ala766Ser, p.Phe814Cys, and p.Ile915Thr had intermediate or wild type values in all assays and showed a predominantly nuclear localization in living cells. All transcriptionally inactive variants (p.Arg609Met, p.Leu701Phe, p.Ser741Tyr, p.Arg775Leu, p.Lys913X) were unable to bind to DNA and were associated with complete AIS. Three variants (p.Asp691del, p.Arg775Leu, p.Ile915Thr) still displayed significant functional activities in in vitro assays, although the clinical phenotype was associated with complete AIS. The data show that molecular phenotyping based on 5 different functional assays matched in most (70%) but not all cases.
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Elfferich
authors.forename: M E
authors.initials: ME
authors.lastname: van Royen
authors.forename: D J
authors.initials: DJ
authors.lastname: van de Wijngaart
authors.forename: J
authors.initials: J
authors.lastname: Trapman
authors.forename: S L S
authors.initials: SL
authors.lastname: Drop
authors.forename: E L T
authors.initials: EL
authors.lastname: van den Akker
authors.forename: S J
authors.initials: SJ
authors.lastname: Lusher
authors.forename: R
authors.initials: R
authors.lastname: Bosch
authors.forename: T
authors.initials: T
authors.lastname: Bunch
authors.forename: I A
authors.initials: IA
authors.lastname: Hughes
authors.forename: A B
authors.initials: AB
authors.lastname: Houtsmuller
authors.forename: M
authors.initials: M
authors.lastname: Cools
authors.forename: S M H
authors.initials: SM
authors.lastname: Faradz
authors.forename: P H
authors.initials: PH
authors.lastname: Bisschop
authors.forename: M C M
authors.initials: MC
authors.lastname: Bunck
authors.forename: W
authors.initials: W
authors.lastname: Oostdijk
authors.forename: H T
authors.initials: HT
authors.lastname: Brüggenwirth
authors.forename: A O
authors.initials: AO
authors.lastname: Brinkmann
mesh_terms: D013734:Androgen-Insensitivity Syndrome / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D011944:Receptors, Androgen / Q000235:genetics*
chemical_list: D011944:Receptors, Androgen