Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity
NC Hornig, M Ukat, HU Schweikert… - The Journal of …, 2016 - academic.oup.com
The Journal of Clinical Endocrinology & Metabolism, 2016•academic.oup.com
Context: Only approximately 85% of patients with a clinical diagnosis complete androgen
insensitivity syndrome and less than 30% with partial androgen insensitivity syndrome can
be explained by inactivating mutations in the androgen receptor (AR) gene. Objective: The
objective of the study was to clarify this discrepancy by in vitro determination of AR
transcriptional activity in individuals with disorders of sex development (DSD) and male
controls. Design: Quantification of DHT-dependent transcriptional induction of the AR target …
insensitivity syndrome and less than 30% with partial androgen insensitivity syndrome can
be explained by inactivating mutations in the androgen receptor (AR) gene. Objective: The
objective of the study was to clarify this discrepancy by in vitro determination of AR
transcriptional activity in individuals with disorders of sex development (DSD) and male
controls. Design: Quantification of DHT-dependent transcriptional induction of the AR target …
Context
Only approximately 85% of patients with a clinical diagnosis complete androgen insensitivity syndrome and less than 30% with partial androgen insensitivity syndrome can be explained by inactivating mutations in the androgen receptor (AR) gene.
Objective
The objective of the study was to clarify this discrepancy by in vitro determination of AR transcriptional activity in individuals with disorders of sex development (DSD) and male controls.
Design
Quantification of DHT-dependent transcriptional induction of the AR target gene apolipoprotein D (APOD) in cultured genital fibroblasts (GFs) (APOD assay) and next-generation sequencing of the complete coding and noncoding AR locus.
Setting
The study was conducted at a university hospital endocrine research laboratory.
Patients
GFs from 169 individuals were studied encompassing control males (n = 68), molecular defined DSD other than androgen insensitivity syndrome (AIS; n = 18), AR mutation-positive AIS (n = 37), and previously undiagnosed DSD including patients with a clinical suspicion of AIS (n = 46).
Intervention(s)
There were no interventions.
Main Outcome Measure(s)
DHT-dependent APOD expression in cultured GF and AR mutation status in 169 individuals was measured.
Results
The APOD assay clearly separated control individuals (healthy males and molecular defined DSD patients other than AIS) from genetically proven AIS (cutoff < 2.3-fold APOD-induction; 100% sensitivity, 93.3% specificity, P < .0001). Of 46 DSD individuals with no AR mutation, 17 (37%) fell below the cutoff, indicating disrupted androgen signaling.
Conclusions
AR mutation-positive AIS can be reliably identified by the APOD assay. Its combination with next-generation sequencing of the AR locus uncovered an AR mutation-negative, new class of androgen resistance, which we propose to name AIS type II. Our data support the existence of cellular components outside the AR affecting androgen signaling during sexual differentiation with high clinical relevance.
Oxford University Press