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

Subject Area Pediatric and Adolescent Medicine
General Genetics and Functional Genome Biology
Biochemistry
Cell Biology
Term from 2017 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 391196622
 
Proper functioning of the androgen receptor (AR) is crucial for the correct development of the male genitalia. Patients with a suspected clinical diagnosis of androgen insensitivity have a male chromosome set (46, XY), male gonads that produce testosterone but undervirilized male genitalia as androgens like testosterone cannot act properly through the AR. The extent of the clinical phenotype of individuals with androgen insensitivity syndrome (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. Only the detection of a partial or complete inactivating mutation in the AR gene is a formal proof of androgen insensitivity so far. 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. Therefore, the identification of other cellular factors whose inactivation via mutations lead to AIS has strong clinical and ethical implications.In a previous research project we established an assay that measures androgen receptor function in human genital skin fibroblasts independently of the presence of mutations in the AR gene. Using this assay we were able to identify a group of patients with androgen insensitivity that show compromised AR function in the absence of AR-gene mutations (referred as AIS type II). We assume that AIS type II derives from genetic changes in co-regulators of the AR leading to its functional reduction and therefore to androgen insensitivity.Aim of this research project is the identification of these co-regulators of AR function through exome- and transcriptome sequencing in clinically and molecularly well characterized genital skin fibroblasts of 24 individuals with AIS type II. Once identified the potential AR-coregulators will be functionally characterized on the molecular level. Furthermore we plan to reverse the phenotype using the CRISPR-Cas technology. This innovative technology will be established for this purpose for the first time in primary genital skin fibroblasts. Finally we want to validate the here identified AR-co-regulators in an independent cohort of unsolved AIS cases from the international database of disorders of sex development (I-DSD) at the University of Glasgow.The here proposed identification of AR-cofactors is not only of major importance for the diagnosis of unsolved androgen insensitivity syndrome it can also have implications on potential therapeutic approaches in other AR-dependent pathologies as prostate cancer, the most frequent malignancy in men.
DFG Programme Research Grants
 
 

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