Epigenetic repression of androgen receptor transcription in mutation-negative androgen insensitivity syndrome (AIS type II)

Nadine C. Hornig*, Pascal Rodens, Helmuth Dörr, Nina C. Hubner, Alexandra E. Kulle, Hans Udo Schweikert, Maik Welzel, Susanne Bens, Olaf Hiort, Ralf Werner, Susanne Gonzalves, Anne Katrin Eckstein, Martine Cools, Annemarie Verrijn-Stuart, Hendrik G. Stunnenberg, Reiner Siebert, Ole Ammerpohl, Paul Martin Holterhus

*Corresponding author for this work
1 Citation (Scopus)


Context: Inactivating mutations within the AR gene are present in only ~40% of individuals with clinically and hormonally diagnosed androgen insensitivity syndrome (AIS). Previous studies revealed the existence of an AR gene mutation–negative group of patients with AIS who have compromised androgen receptor (AR) function (AIS type II). Objective: To investigate whether AIS type II can be due to epigenetic repression of AR transcription. Design: Quantification of AR mRNA and AR proximal promoter CpG methylation levels in genital skin–derived fibroblasts (GFs) derived from patients with AIS type II and control individuals. Setting: University hospital endocrine research laboratory. Patients: GFs from control individuals (n = 11) and patients with AIS type II (n = 14). Main Outcome Measure(s): Measurement of AR mRNA and AR promoter CpG methylation as well as activity of AR proximal promoter in vitro. Results: Fifty-seven percent of individuals with AIS type II (n = 8) showed a reduced AR mRNA expression in their GFs. A significant inverse correlation was shown between AR mRNA abundance and methylation at two consecutive CpGs within the proximal AR promoter. Methylation of a 158-bp-long region containing these CpGs was sufficient to severely reduce reporter gene expression. This region was bound by the runt related transcription factor 1 (RUNX1). Ectopic expression of RUNX1 in HEK293T cells was able to inhibit reporter gene expression through this region.

Conclusions: Aberrant CpGs methylation within the proximal AR promoter plays an important role in the control of AR gene expression and may result in AIS type II. We suggest that transcriptional modifiers, such as RUNX1, could play roles therein offering new perspectives for understanding androgen-mediated endocrine diseases.

Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Issue number12
Pages (from-to)4617-4627
Number of pages11
Publication statusPublished - 01.01.2018

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


Dive into the research topics of 'Epigenetic repression of androgen receptor transcription in mutation-negative androgen insensitivity syndrome (AIS type II)'. Together they form a unique fingerprint.

Cite this