Endocrine Abstracts (2019) 64 001 | DOI: 10.1530/endoabs.64.001

Androgen Insensitivity Syndrome can be due to a dimerization defect in the androgen receptor

S El Kharraz1, C Helsen1, T Hochepied2, C Libert2, D Vanderschueren3 & F Claessens1

1Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, BE-3000 Leuven, Belgium; 2VIB-UGent Center for Inflammation Research, UGent-VIB Research Building FSVM, BE-9052 Gent, Belgium; 3Clinical and Experimental Endocrinology, Department of Endocrinology, University Hospital, BE-3000 Leuven, Belgium.

Mutations in the androgen receptor (AR) are associated with androgen insensitivity syndrome (AIS). Most AIS mutations affect either hormone, DNA or coactivator binding to the AR, but for some mutations there was no explanation yet. Recently, a crystal structure revealed a possible dimerization interface in the ligand binding domain (LBD) of the AR.1 To test the physiological relevance of this LBD dimerization, we generated a mouse model with a W732R mutation located in this interface (further called AR Lmon). The male AR Lmon mice show an external phenotype with a blunt ended vagina, female ano-genital distance and nipple development. Analogous to complete AIS (CAIS), the AR Lmon mice do have intra-abdominal testes but did not developed other reproductive structures. These observations suggest that disruption of dimerization of the AR LBD is crucial for the functioning of the AR. Despite the female-like phenotype, serum concentrations of testosterone and androstenedione are extremely elevated (240 and 75 ng/dl, respectively). The 45-fold increase in serum LH suggests a disruption of the feedback in the hypothalamus-pituitary-gonadal axis, similar to patients with CAIS. The testes of AR Lmon mice show a phenotype that is intermediate between wild type (WT) and AR knock out mice (ARKO). Seminiferous tubules are intermediate in size, hyperplasia of Leydig cells (LC) is observed and despite disrupted functioning of the AR, elongated sperm cells can be found in AR Lmon testes. RNAseq analysis of testes confirmed the differences between WT, AR Lmon and ARKO. The LC-specific Insl3 gene is not expressed in AR Lmon mice. Expression levels of other AR-regulated genes are also reduced, while enzymes involved in androgen synthesis are increased, except for 17-beta-hydroxysteroid dehydrogenase (Hsd17b3), which is responsible for the conversion of androstenedione into testosterone. Luciferase reporter constructs revealed that the Hsd17b3 promotor is controlled by the AR. In bone, however, the phenotype is comparable to ARKO with reduced trabecular and cortical bone. In conclusion, a mouse model of the W732R mutation phenocopies human CAIS, despite the fact that in vitro this mutant AR still can transactivate reporter genes. The corresponding mutation in the human AR was found in two siblings with androgen insensitivity.2 The mouse model also revealed that the AR regulates the final step in testosterone synthesis as it controls the expression of Hsd17b3.

References: 1. Nadal, M. et al. Structure of the homodimeric androgen receptor ligand-binding domain. Nat commun. 8, 14388 (2017).

2. Boehmer, AL. et al. Genotype Versus Phenotype in Families with Androgen Insensitivity Syndrome. J Clin Endocrinol Metab. 86(9), 4151–4160 (2001).

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