Mutations in the amino-terminal domain of the human androgen receptor may be associated with partial androgen insensitivity and impaired transactivation in vitro

• Published in: Experimental and clinical endocrinology & diabetes Vol. 113; no. 8; p. 457
• Main Authors: Holterhus, P-M, Werner, R, Struve, D, Hauffa, B P, Schroeder, C, Hiort, O
• Format: Journal Article
• Language: English
• Published: Germany 01.09.2005
• Subjects: Androgen-Insensitivity Syndrome - genetics; Androgen-Insensitivity Syndrome - metabolism; Animals; Child; CHO Cells; Cricetinae; Cricetulus; Gene Expression - genetics; Gonadal Dysgenesis, 46,XY - genetics; Gonadal Dysgenesis, 46,XY - metabolism; Humans; Infant, Newborn; Male; Mutation; Protein Structure, Tertiary - genetics; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Response Elements - genetics; Transcriptional Activation - genetics
• ISSN: 0947-7349
• DOI: 10.1055/s-2005-865770

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.