Abstract
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:TheAPODassay clearly separated control individuals (healthy malesandmolecular defined DSD patients other than AIS) from genetically proven AIS (cutoff<2.3-foldAPOD-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:ARmutation-positive AIS canbereliably identified by theAPODassay. 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.
| Original language | English |
|---|---|
| Journal | Journal of Clinical Endocrinology and Metabolism |
| Volume | 101 |
| Issue number | 11 |
| Pages (from-to) | 4468-4477 |
| Number of pages | 10 |
| ISSN | 0021-972X |
| DOIs | |
| Publication status | Published - 01.11.2016 |
Funding
This work was supported by the Medical Faculty of the Christian-Albrechts-University, Kiel, Germany (Grant Forschungsförderung 2015-Anschub, to N.H.) and the German Research Council (Deutsche Forschungsgemeinschaft) (Grant Ho 2073/7-1/7-3, to P.-M.H. and Grant Am 343/2-1/2-3, to O.A.). S.F.A. is supported byUKMedical Research Council Partnership Award G1100236. I.A.H. was supported by the National Institute for Health Research Cambridge Biomedical Research Centre. H.U.S. was supported by the German Research Council (Deutsche Forschungsgemeinschaft, DFG). O.H., M.C., L.A., S.F.A., A.E.K., P.-M.H. performed this work also as part of the COST Action BM1303 DSDnet, supported by COST (European Cooperation in Science and Technology)
Research Areas and Centers
- Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
