Han-Jung Lee¹, Irene Mowszowicz², and Chawnshang Chang¹

¹Department of Medicine, and Endocrinology-Reproductive Physiology Program, University of Wisconsin, Comprehensive Cancer Center, Madison, WI 53792

²Biochemistry Laboratory B, Hospital Necker, Paris 75743, France

Received 04/19/96; Accepted 06/10/96; On-line 07/01/96

Androgens play an important role in control of the development of the normal male phenotype and the regulation of virilization in the adult. Various actions of androgens are mediated by an intracellular protein, the androgen receptor (AR), which influences the transcription of androgen-responsive genes. AR, a member of the steroid/thyroid receptor superfamily, acts as a trans-regulator of transcription upon binding with its cognate ligand. This hormone-receptor complex interacts with cis-acting DNA elements to regulate the transcription of its target genes (1). Basically, the structural organization of the AR comprises a variable N-terminal region involved in the modulation of gene expression, a well conserved DNA-binding domain with two zinc fingers, and a partially conserved C-terminal ligand-binding domain (2).

It is noted that absence of a functional AR causes androgen insensitivity syndrome (AIS) with female external phenotypes in 46,XY subjects (3-5). Analysis of the molecular defects of the AR gene in such patients has provided valuable insight into the structural and functional organization of the AR molecule.

In patients with AIS, many mutations in both the DNA- and ligand-binding domains of the AR gene, and just a few cases in the N-terminal region, have been described (3-5). These include mutations in the arginine-614 of the DNA-binding domain and in the valine-888 of the ligand-binding domain in the AR gene of patients with complete androgen insensitivity (CAI) (6, 7). Together, results of these studies have reinforced the concept that AIS is caused by qualitative mutations in the AR gene. Herein, we report, for the first time, the study of two affected siblings among 15 patients with CAI, showing normal wild-type coding sequence of the AR gene with the absence of specific androgen binding.