AG Sex Development

Androgens, especially testosterone and dihydrotestosterone, play a crucial role in the embryonic development of the male reproductive organs and sexual maturation during puberty. Androgens work by binding to the androgen receptor (AR), which is expressed in many tissues, above all the genital organs. The key role of the AR for male sexual differentiation becomes apparent in a syndrome called androgen insensitivity syndrome (AIS), one of the most common forms of differences of sex development (DSD). AIS is classically caused by mutations in the X-chromosomal AR gene leading to reduced or completely absent genital virilization in 46,XY individuals despite normal testicular androgen biosynthesis. Nevertheless, in over 50% of individuals with clinical AIS no AR coding gene mutation can be found. We hypothesize that cofactors of the AR can lead, when mutated, to selective androgen insensitivity. Coregulators have been shown to influence AR activity on many levels, starting from its transcription, folding and inhibition by chaperones, ligand activation, nuclear transport, DNA binding and transactivation of the target genes. In addition, post-translational modifications and chromatin factors can influence its activity (Figure 1). AR cofactors have mainly been identified in the context of prostate cancer research. A developmental and cell type specific composition of AR cofactor complexes in male sex development is largely unknown.

AG-Sex-Development_Abb1 Figure 1: Cofactors of AR-activity act on multiple layers: 1) transcription, 2) folding, 3) post-translational modification, 4) nuclear transport, 5) DNA binding and chromatin factors (NTD: N-terminal domain; LBD: ligand binding domain, ARE: androgen response elements, DHT: dihydrotestosterone)

We previously established an assay that measures AR function in its target tissue namely genital skin fibroblasts (GFs). Using this assay we identified a group of GFs with reduced AR function in the absence of an AR coding gene mutation (AIS type II). Our main research focus is the identification of the molecular factors (AR cofactors) leading to AIS type II. This will help not only to significantly improve the diagnosis in affected individuals but also push forward the molecular understanding of human male sex differentiation which is still largely unclear.

Selected publications:

Molecular basis of androgen insensitivity syndromes. Hornig NC, Holterhus PM. Mol Cell Endocrinol. 2021 Mar 1;523:111146. doi: 10.1016/j.mce.2020.111146.

Reduced Androgen Receptor Expression in Genital Skin Fibroblasts From Patients With 45,X/46,XY Mosaicism. Hornig NC, Demiri J, Rodens P, Murga Penas EM, Caliebe A, Eckstein AK, Schweikert HU, Audi L, Hiort O, Werner R, Kulle AE, Ammerpohl O, Holterhus PM. J Clin Endocrinol Metab. 2019 Oct 1;104(10):4630-4638. doi: 10.1210/jc.2019-00108.

Epigenetic Repression of Androgen Receptor Transcription in Mutation-Negative Androgen Insensitivity Syndrome (AIS Type II). Hornig NC, Rodens P, Dörr H, Hubner NC, Kulle AE, Schweikert HU, Welzel M, Bens S, Hiort O, Werner R, Gonzalves S, Eckstein AK, Cools M, Verrijn-Stuart A, Stunnenberg HG, Siebert R, Ammerpohl O, Holterhus PM. J Clin Endocrinol Metab. 2018 Dec 1;103(12):4617-4627. doi: 10.1210/jc.2018-00052.

Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity. Hornig NC, Ukat M, Schweikert HU, Hiort O, Werner R, Drop SL, Cools M, Hughes IA, Audi L, Ahmed SF, Demiri J, Rodens P, Worch L, Wehner G, Kulle AE, Dunstheimer D, Müller-Roßberg E, Reinehr T, Hadidi AT, Eckstein AK, van der Horst C, Seif C, Siebert R, Ammerpohl O, Holterhus PM. J Clin Endocrinol Metab. 2016 Nov;101(11):4468-4477. doi: 10.1210/jc.2016-1990.

A Recurrent Germline Mutation in the 5'UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation. Hornig NC, de Beaufort C, Denzer F, Cools M, Wabitsch M, Ukat M, Kulle AE, Schweikert HU, Werner R, Hiort O, Audi L, Siebert R, Ammerpohl O, Holterhus PM. PLoS One. 2016 Apr 25;11(4):e0154158. doi: 10.1371/journal.pone.0154158.


PD Dr. rer. nat. Nadine Hornig

Wissenschaftliche Mitarbeiterin, Molekularbiologin
Tel.: 0431 500-30616