Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity
| العنوان: | Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity |
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| المؤلفون: | Hornig, N. C., Ukat, M., Schweikert, H. U., Hiort, O., Werner, R., Drop, S. L. S., Cools, Martine, Hughes, I. A., Audi, L., Ahmed, S. F., Demiri, J., Rodens, P., Worch, L., Wehner, G., Kulle, A. E., Dunstheimer, D., Müller-Roßberg, E., Reinehr, T., Hadidi, A. T., Eckstein, A. K., van der Horst, C., Seif, C., Siebert, R., Ammerpohl, O., Holterhus, P.-M. |
| المساهمون: | Pediatrics |
| المصدر: | The Journal of Clinical Endocrinology and Metabolism Journal of Clinical Endocrinology and Metabolism, 101(11), 4468-4477. Endocrine Society JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM |
| بيانات النشر: | Endocrine Society, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Adult, Male, APOLIPOPROTEIN-D, Transcription, Genetic, DISORDERS, Disorders of Sex Development, XY DSD, MOSAICISM, Sensitivity and Specificity, CLONING, Medicine and Health Sciences, Humans, Testosterone, MOLECULAR-SPECTRUM, Apolipoproteins D, Cells, Cultured, SEX DEVELOPMENT, High-Throughput Nucleotide Sequencing, Original Articles, COREGULATORS, Androgen-Insensitivity Syndrome, Fibroblasts, PROSTATE-CANCER, RECEPTOR GENE-MUTATIONS, Receptors, Androgen, Mutation, Biological Assay |
| الوصف: | 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. The use of Apolipoprotein D as a biomarker for androgen sensitivity identifies a new type of androgen insensitivity syndrome that is not associated with a mutation in the androgen receptor gene. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1945-7197 0021-972X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::f511ef3a4ceb09725e98ed14a20ae78d http://europepmc.org/articles/PMC5095254 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.pmid.dedup....f511ef3a4ceb09725e98ed14a20ae78d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19457197 0021972X |
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