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 con...

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Bibliographic Details
Published in:PloS one 2009-12, Vol.4 (12), p.e8179
Main Authors: Szafran, Adam T, Hartig, Sean, Sun, Huiying, Uray, Ivan P, Szwarc, Maria, Shen, Yuqing, Mediwala, Sanjay N, Bell, Jennifer, McPhaul, Michael J, Mancini, Michael A, Marcelli, Marco
Format: Article
Language:English
Subjects:
Abnormalities
Amino Acid Substitution - genetics
Androgen receptors
Androgen-Insensitivity Syndrome - genetics
Androgens
Cell Biology
Cell Biology/Cell Growth and Division
Cell Biology/Cell Signaling
Cell Biology/Developmental Molecular Mechanisms
Cell Biology/Gene Expression
Cell Biology/Morphogenesis and Cell Biology
Cell Biology/Nuclear Structure and Function
Cell cycle
Cell lines
Cell Nucleus - metabolism
Cellular biology
Content analysis
Dose-Response Relationship, Drug
Drug dosages
Fibroblasts
Fibroblasts - metabolism
Gender
Genetic aspects
Genetics and Genomics/Gene Expression
Genetics and Genomics/Genetics of Disease
Genetics and Genomics/Nuclear Structure and Function
Genomes
HeLa Cells
High-Throughput Screening Assays - methods
Humans
Ligands
Male
Males
Medicine
Mutant Proteins - metabolism
Mutation
Mutation - genetics
Patients
Precision medicine
Precision Medicine - methods
Prostate cancer
Protein Structure, Tertiary
Protein Transport
Proteins
Qualitative research
Rare diseases
Receptors, Androgen - chemistry
Receptors, Androgen - genetics
Sex differentiation
Skin
Testosterone
Transcription, Genetic
Viability
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Description
Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0008179