A deep intronic mutation in AR gene causing androgen insensitivity syndrome: difficulties of diagnostics

Partial androgen resistance syndrome (PAIS) is the most difficult form of disorders/differences of sex development 46,XY (DSD 46,XY) for choosing of patient management. To date, there are no clear biochemical criteria, especially before puberty, that allow differentiating PAIS from other PAIS-like forms of DSD 46, XY, and genetic verification of the partial form of AIS plays an important role. Meanwhile, according to the literature, mutations in the coding region of AR gene have not been identified in more than 50% of patients with suspected AIS. We performed an extensive analysis of the AR gene in a patient with clinical and laboratory signs of AIS and found a deep intron mutation in the AR gene (p. 2450–42G>A). This variant creates an alternative splice acceptor site resulted a disturbance of the AR function. These findings indicate the need for extensive genetic analysis in a cohort of patients with suspected CPA in the absence of mutations in the AR gene using standard methods of genetic diagnosis.

Inferring Differential Networks by Integrating Gene Expression Data With Additional Knowledge

Evidences increasingly indicate the involvement of gene network rewiring in disease development and cell differentiation. With the accumulation of high-throughput gene expression data, it is now possible to infer the changes of gene networks between two different states or cell types via computational approaches. However, the distribution diversity of multi-platform gene expression data and the sparseness and high noise rate of single-cell RNA sequencing (scRNA-seq) data raise new challenges for existing differential network estimation methods. Furthermore, most existing methods are purely rely on gene expression data, and ignore the additional information provided by various existing biological knowledge. In this study, to address these challenges, we propose a general framework, named weighted joint sparse penalized D-trace model (WJSDM), to infer differential gene networks by integrating multi-platform gene expression data and multiple prior biological knowledge. Firstly, a non-paranormal graphical model is employed to tackle gene expression data with missing values. Then we propose a weighted group bridge penalty to integrate multi-platform gene expression data and various existing biological knowledge. Experiment results on synthetic data demonstrate the effectiveness of our method in inferring differential networks. We apply our method to the gene expression data of ovarian cancer and the scRNA-seq data of circulating tumor cells of prostate cancer, and infer the differential network associated with platinum resistance of ovarian cancer and anti-androgen resistance of prostate cancer. By analyzing the estimated differential networks, we find some important biological insights about the mechanisms underlying platinum resistance of ovarian cancer and anti-androgen resistance of prostate cancer.

Adolescent Gynecomastia due to Minimal Androgen Resistance Syndrome: A Case Report and Literature Review

A 14-year-old boy with a 46,XY karyotype and persistent breast-3-stage gynecomastia is reported. The reproductive axis was investigated by standard laboratory methods and the androgen receptor (AR) gene was sequenced. Also, a literature review of phenotypes associated with the AR genetic variant p.Pro392Ser was performed. The boy presented with height in the upper normal range (+1.9 SDS) and normal body mass index (−0,3 SDS); pubertal development was PH5/G4 (mean testicular volume 15 mL; 0 SDS). Laboratory findings were normal for age and sex, except aromatization index (0.09; reference range 0.03–0.07). Analysis of the AR gene showed the single nucleotide variant c.1174C>T (p.Pro392Ser) in exon 1, leading to the diagnosis of minimal androgen insensitivity syndrome (AIS). This genetic variant is reported in other 8 patients with AIS and is associated with variable clinical phenotypes ranging from complete to partial and minimal AIS. To the best of our knowledge, this is the first adolescent in whom the p.Pro392Ser mutation is associated with isolated persistent gynecomastia. The underlying reason of phenotypic variability due to this AR mutation remains unknown. Persistent gynecomastia due to minimal AIS has been reported in few additional males with variable AR mutations. Since fertility troubles may occur in adult men with minimal AIS, early diagnosis can allow optimizing the clinical management.

A clinical case of partial androgen resistance syndrome (Reifenstein syndrome)

In the paper we describe a clinical case and provide integrated clinical and laboratory data of a patient with partial androgen resistance syndrome. A 25-year-old male was referred for medical evaluation for an infertile marriage. After a comprehensive assessment, he was diagnosed with hypergonadotropic hypogonadism, coronal hypospadia, left-sided varicocele, and oligoasthenoteratozoospermia. Cytogenetic analysis showed normal male karyotype (46,XY). Molecular genetic analysis identified the c.731_736delCGGTGT mutation in the exon 1 of the androgen receptor (AR) gene, what allowed for making a diagnosis of Reifenstein syndrome. In addition, we give a brief literature review of the clinical conditions associated with abnormal androgen sensitivity and discuss the problems of testing and counseling of patients with partial androgen resistance syndrome.

Bardoxolone-Methyl (CDDO-Me) Suppresses Androgen Receptor and Its Splice-Variant AR-V7 and Enhances Efficacy of Enzalutamide in Prostate Cancer Cells

Androgen receptor (AR) signaling is fundamental to prostate cancer (PC) progression, and hence, androgen deprivation therapy (ADT) remains a mainstay of treatment. However, augmented AR signaling via both full length AR (AR-FL) and constitutively active AR splice variants, especially AR-V7, is associated with the recurrence of castration resistant prostate cancer (CRPC). Oxidative stress also plays a crucial role in anti-androgen resistance and CRPC outgrowth. We examined whether a triterpenoid antioxidant drug, Bardoxolone-methyl, known as CDDO-Me or RTA 402, can decrease AR-FL and AR-V7 expression in PC cells. Nanomolar (nM) concentrations of CDDO-Me rapidly downregulated AR-FL in LNCaP and C4-2B cells, and both AR-FL and AR-V7 in CWR22Rv1 (22Rv1) cells. The AR-suppressive effect of CDDO-Me was evident at both the mRNA and protein levels. Mechanistically, acute exposure (2 h) to CDDO-Me increased and long-term exposure (24 h) decreased reactive oxygen species (ROS) levels in cells. This was concomitant with an increase in the anti-oxidant transcription factor, Nrf2. The anti-oxidant N-acetyl cysteine (NAC) could overcome this AR-suppressive effect of CDDO-Me. Co-exposure of PC cells to CDDO-Me enhanced the efficacy of a clinically approved anti-androgen, enzalutamide (ENZ), as evident by decreased cell-viability along with migration and colony forming ability of PC cells. Thus, CDDO-Me which is in several late-stage clinical trials, may be used as an adjunct to ADT in PC patients.