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Exp Clin Endocrinol Diabetes 2005; 113(8): 457-463
DOI: 10.1055/s-2005-865770
Article

J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Mutations in the Amino-Terminal Domain of the Human Androgen Receptor may be Associated with Partial Androgen Insensitivity and Impaired Transactivation in vitro [1]

P.-M. Holterhus1 , R. Werner1 , D. Struve1 , B. P. Hauffa2 , C. Schroeder3 , O. Hiort1
  • 1Department of Pediatrics, University-Hospital of Schleswig-Holstein, Campus Lübeck, Germany
  • 2Department of Pediatrics, University Hospital Essen, Germany
  • 3Department of Pediatrics, University Hospital Greifswald, Germany
Further Information

Publication History

Received: January 11, 2005 First decision: April 18, 2005

Accepted: May 23, 2005

Publication Date:
08 September 2005 (online)

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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)2TATA 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.

Key words

Androgen insensitivity - androgen receptor - transactivation - reporter gene - genetics - ambiguous genitalia - androgen-regulated genes

1 Supported by DFG-grant KFO 111/1

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1 Supported by DFG-grant KFO 111/1

Professor Dr. med. Olaf Hiort

Department of Pediatrics and Adolescent Medicine
Division of Pediatric Endocrinology and Diabetes
Universitätsklinikum Schleswig-Holstein
Campus Lübeck

Ratzeburger Allee 160

23538 Lübeck

Germany

Phone: + 494515002191

Fax: + 49 45 15 00 68 67

Email: hiort@paedia.ukl.mu-luebeck.de