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Published on: December 15, 2017
Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity
N C Hornig1, M Ukat1, H U Schweikert1
1Department of Pediatrics (N.C.H., M.U., J.D., P.R., A.E.K., P.-M.H.), Division of Pediatric Endocrinology and Diabetes, and Institute of Human Genetics (L.W., R.S., O.A.), Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Schwanenweg 20, 24105 Kiel, Germany; Rheinische Friedrich-Wilhelms-Universität Bonn, Department of Medicine III (H.U.S., G.W.), Institute for Biochemistry and Molecular Biology, Nussallee 11, 53115 Bonn, Germany; Department of Pediatrics (O.H., R.W.), Division of Experimental Pediatric Endocrinology, University of Luebeck, 23538 Luebeck, Germany; Department of Pediatrics (S.L.S.D.), Division of Pediatric Endocrinology, Sophia Childreńs Hospital, Erasmus Medical Center, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands; Department of Pediatric Endocrinology (Medical Center), Ghent University Hospital, Ghent University, 9000 Ghent, Belgium; Department of Pediatrics (I.A.H.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Pediatric Endocrinology Research Unit (L.A.), Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Centro de Investigación Biomédica en Red Enfermedades Raras, Instituto de Salud Carlos III, Passeig Vall d'Hebron 119, 08035 Barcelona, Spain; Developmental Endocrinology Research Group (S.F.A.), School of Medicine, University of Glasgow, Yorkhill Glasgow G3 8SJ, United Kingdom; Kinderklinik (D.D.), Klinikum Augsburg, 86156 Augsburg, Germany; Klinikum Esslingen (E.M.-R.), 73730 Esslingen, Germany; Department of Pediatrics (T.R.), Division of Pediatric Endocrinology, Diabetes, and Nutrition, University Witten/Herdecke, 45711 Datteln, Germany; Hypospadiezentrum (A.T.H.), 63500 Seligenstadt, Germany; Gemeinschaftspraxis für Kinderchirurgie (A.K.E.), 24119 Kronshagen, Germany; Urologische Gemeinschaftspraxis (C.v.d.H), and UROLOGIE Zentrum Kiel (C.S.), 24103 Kiel, Germany; and Institute of Human Genetics (R.S.), University of Ulm and University Hospital of Ulm, 89081 Ulm, Germany.
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.
