Endocrine Abstracts (2016) 42 OC4 | DOI: 10.1530/endoabs.42.OC4

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

Nadine C Hornig1, Martine Ukat1, Hans-Udo Schweikert2, Olaf Hiort3, Ralf Werner3, Stenvert LS Drop4, Martine Cools5, Ieuan A Hughes6, Laura Audi7, S Faisal Ahmed8, Jeta Demiri1, Pascal Rodens1, Lisa Worch9, Gaby Wehner2, Alexandra E Kulle1, Desiree Dunstheimer10, Elke Müller-Roßberg11, Thomas Reinehr12, Ahmed T Hadidi13, Anne K Eckstein14, Christof van der Horst15, Christoph Seif16, Reiner Siebert17, Ole Ammerpohl9 & Paul-Martin Holterhus1

1Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Schwanenweg 20, 24105 Kiel, Germany; 2Department of Medicine III, Institute for Biochemistry and Molecular Biology, University Bonn, Nussallee 11, 53115 Bonn, Germany; 3Department of Pediatrics, Division of Experimental Pediatric Endocrinology, University Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany; 4Department of Pediatrics, Division of Pediatric Endocrinology, Sophia Children’s Hospital, Erasmus MC, ’s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands; 5Department of Pediatric Endocrinology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; 6Department of Pediatrics, University of Cambridge, Hills Road, Cambridge CB2 0QQ, UK; 7Pediatric Endocrinology Research Unit, VHIR (Vall d’Hebron Institut de Recerca), Hospital Universitari Vall d’Hebron, CIBERER (Center for Biomedical Research on Rare Diseases), Instituto de Salud Carlos III, Passeig Vall d’Hebron 119 -- 08035 Barcelona, Spain; 8Developmental Endocrinology Research Group, School of Medicine, University of Glasgow, Yorkhill Glasgow G3 8SJ, UK; 9Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Schwanenweg 24, 24105 Kiel, Germany; 10Kinderklinik, Klinikum Augsburg, Stenglinstr. 2, 86156 Augsburg, Germany; 11Klinikum Esslingen, Hirschlandstr. 97, 73730 Esslingen, Germany; 12Department of Pediatrics, Division of Pediatric Endocrinology, Diabetes and Nutrition, University. Witten/Herdecke, Dr. F. Steiner Str. 5, 45711 Datteln, Germany; 13Hypospadiezentrum, Frankfurter Str. 51, 63500 Seligenstadt, Germany; 14Gemeinschaftspraxis für Kinderchirurgie, Eichkoppelweg 74, 24119 Kronshagen, Germany; 15Urologische Gemeinschaftspraxis, Prüner Gang 15, 24103 Kiel, Germany; 16UROLOGIE Zentrum Kiel, Alter Markt 11, 24103 Kiel, Germany; 17Institute of Human Genetics, University Hospital of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany

Although androgen insensitivity syndrome (AIS) is commonly suspected as a cause of a 46,XY disorder of sex development (DSD), only about half of these cases can be attributed to an inactivating mutation within the coding sequence (CDS) of the androgen receptor (AR) gene. This led to the hypothesis that disrupted AR activation in AIS may also be caused by a defect in a co-factor of AR-activity. However, so far mutations in AR co-factors leading to AIS have not been identified. To further investigate this discrepancy between genotype and phenotype, we have evaluated the dihydrotestosterone (DHT) dependent AR-induced expression of apolipoprotein D (APOD) in cultured genital skin fibroblast (GF) as a measure of the AR transcriptional activity in a total of 169 individuals. Using this “APOD assay” we were able to define a cut-off value that distinguishes AR transcriptional activity in GF from individuals with genetically confirmed AIS bearing a mutation in the AR-CDS and a male control group without any DSD with high significance (P<0.0001). When this cut-off was applied to GF derived from individuals with suspected AIS who did not have a mutation in the AR-CDS, we were able to identify a subgroup (n=17) with significantly reduced AR function. This subgroup strongly supports the existence of genetic factors outside the AR, e.g. in regulatory regions or co-factors, compromising AR-activity in AIS.

Funding: DFG (Ho 2073/7-1/7-3 and Am 343/2-1/2-3)

Presenting Author: Nadine C. Hornig, Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Schwanenweg 20, 24105 Kiel, Germany. Email: nhornig@medgen.uni-kiel.de

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