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: firstname.lastname@example.org