Three novel and two known androgen receptor gene mutations associated with androgen insensitivity syndrome in sex-reversed XY female patients

Balachandran, Saranya; Bhavani, Gunasekaran; Arumugam, Brindha; Jayashankar, M. R.; Santhiya, S.

doi:10.1007/s12041-016-0716-0

Cited by 5 publications

(3 citation statements)

References 45 publications

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“…Pathogenic variants in the LBD were present in 13/19 (68.4%) followed by 3/19 (15.8%) in the NTD and DBD each. Similar findings have been noted previously [Gottlieb et al, 2012;Saranya et al, 2016;Yuan et al, 2018], suggesting that the LBD is more susceptible to being a hotspot region for pathogenic variants in patients with AIS.…”

Section: Discussionsupporting

confidence: 89%

“…More than 1,100 different pathogenic variants including deletions, duplications, insertions, and point variants have been documented in the AR gene (www.androgendb.mcgill.ca), with the majority being missense pathogenic variants. There are very few studies from India on clinical, biochemical, and molecular aspects of AIS, the majority being case reports [Abilash et al, 2016;Saranya et al, 2016;Akella, 2017], and no hotspot pathogenic variant has been identified [Nagaraja et al, 2010].…”

Section: Introductionmentioning

confidence: 99%

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Clinical, Biochemical, and Molecular Characterization of Indian Children with Clinically Suspected Androgen Insensitivity Syndrome

Kumar

Sharma

Faruq

et al. 2021

Sex Dev

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This study describes the clinical, biochemical, and molecular characteristics of Indian children with 46,XY DSD and suspected androgen insensitivity syndrome (AIS). Fifty children (median age 3.0 years, range 0–16.5 years) with 46,XY DSD and a suspected diagnosis of AIS were enrolled. Sanger sequencing was performed to identify pathogenic variants in the androgen receptor (AR) gene and to study genotype-phenotype correlations. All 5 (100%) patients with CAIS and 14/45 (31%) patients with PAIS had pathogenic/likely pathogenic variants in the AR gene (overall, 14 different variants in 19 patients; 38.8%). There was no significant difference in clinical (cryptorchidism, hypospadias, or external masculinizing score) or biochemical parameters (gonadotropins and testosterone) between patients with or without pathogenic variants. However, patients with AIS were more likely to have a positive family history, be assigned female gender at birth, and present with gynaecomastia at puberty. Three novel pathogenic/likely pathogenic variants, including one splice donor site variant c.2318+1G>A, one frameshift variant p.H790Lfs*40, and one missense variant p.G821E, were identified in 3 patients with CAIS. The missense variant p.G821E was predicted as deleterious, damaging, disease-causing, and likely functionally inactive by in silico analysis and protein modelling study. Two previously not reported pathogenic/likely pathogenic variants, including p.R386H and p.G396R, were identified in patients with PAIS. This study contributes in expanding the spectrum of pathogenic variants in the AR gene in patients with AIS. Only 31% patients with a provisional diagnosis of PAIS had pathogenic variants in the AR gene, suggesting other possible mechanisms or candidate genes may be responsible for such a phenotypic presentation.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Clinical, Biochemical, and Molecular Characterization of Indian Children with Clinically Suspected Androgen Insensitivity Syndrome

Kumar

Sharma

Faruq

et al. 2021

Sex Dev

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“…AIS is the most common cause of the 46,XY disorder in sex development. − Point mutations within the AR LBD are frequently described in this disease . The AR LBD possesses a three-layer sandwich fold architecture (Figure S1A).…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule Inhibition of Androgen Receptor Dimerization as a Strategy against Prostate Cancer

Yang

et al. 2023

ACS Cent. Sci.

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The clinically used androgen receptor (AR) antagonists for the treatment of prostate cancer (PCa) are all targeting the AR ligand binding pocket (LBP), resulting in various drug-resistant problems. Therefore, a new strategy to combat PCa is urgently needed. Enlightened by the gain-of-function mutations of androgen insensitivity syndrome, we discovered for the first time small-molecule antagonists toward a prospective pocket on the AR dimer interface named the dimer interface pocket (DIP) via molecular dynamics (MD) simulation, structure-based virtual screening, structure−activity relationship exploration, and bioassays. The first-in-class antagonist M17-B15 targeting the DIP is capable of effectively disrupting AR self-association, thereby suppressing AR signaling. Furthermore, M17-B15 exhibits extraordinary anti-PCa efficacy in vitro and also in mouse xenograft tumor models, demonstrating that AR dimerization disruption by small molecules targeting the DIP is a novel and valid strategy against PCa.

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Disorders of Sexual Development

Babbar¹,

Shah²,

Abelson³

et al. 2020

Comprehensive Care of the Transgender Patient

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Three novel and two known androgen receptor gene mutations associated with androgen insensitivity syndrome in sex-reversed XY female patients

Cited by 5 publications

References 45 publications

Clinical, Biochemical, and Molecular Characterization of Indian Children with Clinically Suspected Androgen Insensitivity Syndrome

Clinical, Biochemical, and Molecular Characterization of Indian Children with Clinically Suspected Androgen Insensitivity Syndrome

Small-Molecule Inhibition of Androgen Receptor Dimerization as a Strategy against Prostate Cancer

Disorders of Sexual Development

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