ESPE Yearbook of Paediatric Endocrinology

Brief summary: This ex vivo/ in vitro study describes a novel regulatory mechanism of androgen receptor (AR) gene transcription by intranuclear actin assembly in droplets upon dihydrotestosterone (DHT) stimulation mediated by DAAM2 (Dishevelled-associated activator of morphogenesis 2) gene.

Androgen insensitivity syndrome (AIS) is a common etiology in individuals with 46, XY disorder/differences of sex development, AIS has diverse genital phenotypes. Complete androgen insensitivity syndrome (CAIS), is presented with XY sex reversal with normal female phenotype, whereas phenotype diversity is variable with residual androgen receptor activity, which leads to partial androgen insensitivity syndrome (PAIS). Various pathogenic variants within the androgen receptor (AR) gene on the X chromosome are the primary pathogenesis of AIS. The majority of clinically diagnosed CAIS can be explained by inactivating mutations in the AR, this is true for less than half of cases with the clinical diagnosis of PAIS. The AR mutation-negative group of AIS characterized by significantly lower AR activity in its human target tissues such as genital skin fibroblasts (GSFs), is named AIS type II. Knerr J et al. identified heterozygous variants in the DAAM2 gene in two unrelated individuals with AIS type II. They have studied the role of DAAM2 in the pathogenesis of AIS.

DAAM2 belongs to the formin family of cytoskeletal regulators which is involved in nucleation and polymerization of actin. In this study, Knerr J et al. showed that DAAM2 appear as small spots dispersed within the nuclear compartment which increase in both number and size following stimulation with DHT. DHT signalling drives actin-dependent colocalization of DAAM2, AR and active RNA Polymerase II. DAAM2 and AR colocalize to form droplet-like assemblies in both a signal- and actin polymerization-dependent manner which subsequently associate with active RNA Polymerase II to facilitate testosterone-stimulated gene expression. Overall this study demonstrates that DAAM2-mediated actin assembly drives AR clustering for transcriptionally active droplet formation in response to DHT.

This mechanism provides further insight for the pathogenesis of AIS and also highlight DAAM2 as a potential pharmacological target for AR-related diseases.