A mutation in the DNA-binding domain of the androgen receptor gene causes complete testicular feminization in a patient with receptor-positive androgen resistance.
Androgen resistance is associated with a wide range of quantitative and qualitative defects in the androgen receptor. However, fibroblast cultures from approximately 10% of patients with the clinical, endocrine, and genetic features characteristic of androgen resistance express normal quantities of apparently normal androgen receptor in cultured genital skin fibroblasts (receptor-positive androgen resistance). We have analyzed the androgen receptor gene of one patient (P321) with receptor-positive, complete testicular feminization and detected a single nucleotide substitution at nucleotide 2006 (G----C) within the second "zinc finger" of the DNA-binding domain that results in the conversion of the arginine residue at position 615 into a proline residue. Introduction of this mutation into the androgen receptor cDNA and transfection of the expression plasmid into eukaryotic cells lead to the synthesis of a receptor protein that displays normal binding kinetics but is inactive in functional assays of receptor activity. We conclude that substitution mutations in the DNA-binding domain of the androgen receptor are one cause of "receptor-positive" androgen resistance.
Marcelli
M
M
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8857.
Zoppi
S
S
Grino
P B
PB
Griffin
J E
JE
Wilson
J D
JD
McPhaul
M J
MJ
D013734:Androgen-Insensitivity Syndrome / Q000235:genetics*; D001483:Base Sequence; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D013196:Dihydrotestosterone / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009841:Oligonucleotides / Q000737:chemistry; D016133:Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics / Q000502:physiology*; D013329:Structure-Activity Relationship; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D009841:Oligonucleotides; D011944:Receptors, Androgen; D013196:Dihydrotestosterone