title: Mutations in the amino-terminal domain of the human androgen receptor may be associated with partial androgen insensitivity and impaired transactivation in vitro.
abstract: The majority of genetic variations in the androgen receptor (AR) gene are point mutations leading to impairment of the DNA- or hormone-binding domains. The N-terminus encoded by the first exon of the AR-gene usually harbors disruptive mutations associated with complete androgen insensitivity syndrome (CAIS) while missense mutations related with partial androgen insensitivity syndrome (PAIS) are seemingly rare. We present a 46,XY male with scrotal hypospadias in whom we detected a S432 F point mutation within the N-terminus. Transient transfections of an AR expression plasmid carrying the S432 F mutation using Chinese Hamster Ovary (CHO) cells revealed a significant partial reduction in transactivation of the co-transfected androgen responsive (ARE) (2)TATA luciferase reporter gene thus confirming PAIS. In two further 46, XY patients with slight to moderate virilization defects, we detected an S411 N mutation, and a 9 base pair deletion leading to the loss of amino acids 409 to 411 (L-A-S), respectively. These mutations did not compromise AR-function under the chosen experimental settings. The S432 F-patient supports particular significance of the AR-N-terminus for mild forms of AIS while the functional role of the two further mutations remains unclear. The N-terminus is a species-specific AR-domain possibly also involved in contributing to target tissue selectivity of AR-actions via mediating co-regulator interactions. Therefore, mild molecular defects of the AR-N-terminus may not necessarily inhibit general transactivation properties using currently established reporter gene models.
authors.affiliation: Department of Pediatrics, University-Hospital of Schleswig-Holstein, Campus Lübeck, Germany.
authors.forename: P-M
authors.initials: PM
authors.lastname: Holterhus
authors.forename: R
authors.initials: R
authors.lastname: Werner
authors.forename: D
authors.initials: D
authors.lastname: Struve
authors.forename: B P
authors.initials: BP
authors.lastname: Hauffa
authors.forename: C
authors.initials: C
authors.lastname: Schroeder
authors.forename: O
authors.initials: O
authors.lastname: Hiort
mesh_terms: D013734:Androgen-Insensitivity Syndrome / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002648:Child; D006224:Cricetinae; D003412:Cricetulus; D015870:Gene Expression / Q000235:genetics; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D017434:Protein Structure, Tertiary / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: D011944:Receptors, Androgen