Identification of highly selective co-regulators of the androgen receptor based on a functional in vitro model of androgen insensitivity

• Applicant: Privatdozentin Dr. Nadine Hornig
• Subject Area: Pediatric and Adolescent Medicine ; General Genetics and Functional Genome Biology ; Endocrinology, Diabetology, Metabolism ; Human Genetics
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467366593

The androgen receptor (AR) plays an essential role during male sex development. Patients with a suspected clinical diagnosis of androgen insensitivity syndrome (AIS) have a male chromosome set (46, XY), testosterone producing testes but undervirilized male genitalia as androgens like testosterone cannot act properly through the AR. The extent of the clinical phenotype of individuals with AIS depends on the remaining activity of the AR and ranges from complete androgen insensitivity with complete female appearance over partial androgen insensitivity with undervirilized external genitalia to mild androgen insensitivity with associated gynecomastia and infertility. A molecularly proven diagnosis of AIS depends on the detection of a partial or complete inactivating mutation in the AR-gene. Nevertheless, less than half of individuals with the clinical diagnosis of androgen insensitivity bear a mutation in the AR-gene. This makes the counseling and clinical care of individuals with AIS in the absence of an AR-gene mutation difficult and raises questions as fundamental as gender assignment. The aim of this research proposal is the identification and functional characterization of AR-coregulatory factors causing AR-mutation negative AIS in order to broaden current (patho-) physiological models of cellular androgen signaling especially regarding differences of sex development.The identification of these coregulators of AR function was achieved through exome sequencing in clinically and molecularly well characterized genital skin fibroblasts of 26 individuals with AIS type II in the current research project (HO 6028/2-1) and validation experiments were performed. The aim of the here presented renewal proposal is to fully functionally characterize selected potential AR-coregulators. In collaboration with the international database of disorders of sex development (I-DSD) at the University of Glasgow we aim to validate the here identified AR-coregulators in an independent cohort of unsolved AIS cases.The here proposed identification of AR-cofactors is not only of major importance for the diagnosis of unsolved androgen insensitivity syndrome, it also contributes significantly to a better understanding of sex development and differences therein. Furthermore, it has potential implications on therapeutic approaches in other AR-dependent pathologies like prostate cancer, the most frequent malignancy in men.

• DFG Programme: Research Grants