Androgen receptor mutations associated with androgen insensitivity syndrome: a high content analysis approach leading to personalized medicine.
Androgen insensitivity syndrome (AIS) is a rare disease associated with inactivating mutations of AR that disrupt male sexual differentiation, and cause a spectrum of phenotypic abnormalities having as a common denominator loss of reproductive viability. No established treatment exists for these conditions, however there are sporadic reports of patients (or recapitulated mutations in cell lines) that respond to administration of supraphysiologic doses (or pulses) of testosterone or synthetic ligands. Here, we utilize a novel high content analysis (HCA) approach to study AR function at the single cell level in genital skin fibroblasts (GSF). We discuss in detail findings in GSF from three historical patients with AIS, which include identification of novel mechanisms of AR malfunction, and the potential ability to utilize HCA for personalized treatment of patients affected by this condition.
Szafran
Adam T
AT
Department of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
Hartig
Sean
S
Sun
Huiying
H
Uray
Ivan P
IP
Szwarc
Maria
M
Shen
Yuqing
Y
Mediwala
Sanjay N
SN
Bell
Jennifer
J
McPhaul
Michael J
MJ
Mancini
Michael A
MA
Marcelli
Marco
M
D019943:Amino Acid Substitution / Q000235:genetics; D013734:Androgen-Insensitivity Syndrome / Q000235:genetics*; D000728:Androgens; D002467:Cell Nucleus / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D006367:HeLa Cells; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008297:Male; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D057285:Precision Medicine / Q000379:methods*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics*; D014158:Transcription, Genetic
C410798:AR protein, human; D000728:Androgens; D050505:Mutant Proteins; D011944:Receptors, Androgen