LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome.

Androgen insensitivity syndrome (AIS) is a difference of sex development (DSD) characterized by different degrees of undervirilization in individuals with a 46,XY karyotype despite normal to high gonadal testosterone production. Classically, AIS is explained by hemizygous mutations in the X-chromosomal androgen receptor (AR) gene. Nevertheless, the majority of individuals with clinically diagnosed AIS do not carry an AR gene mutation.

The past and future of "sex genes".

Much later than the discovery of "sex chromosomes" and of "sex hormones", genetics started delivering detailed explanations of sex-determining developmental pathways. Despite increasing knowledge of biological processes, concepts and theories about sex development are never based on facts alone. There are inevitable entanglements of biological description and changing cultural assumptions and they play a key role in how sex genes are framed and interpreted in biological research.

Formin-mediated nuclear actin at androgen receptors promotes transcription.

Steroid hormone receptors are ligand-binding transcription factors essential for mammalian physiology. The androgen receptor (AR) binds androgens mediating gene expression for sexual, somatic and behavioural functions, and is involved in various conditions including androgen insensitivity syndrome and prostate cancer. Here we identified functional mutations in the formin and actin nucleator DAAM2 in patients with androgen insensitivity syndrome.

Can Non-Coding NR5A1 Gene Variants Explain Phenotypes of Disorders of Sex Development?

Introduction: NR5A1 is an essential transcription factor that regulates several target genes involved in reproduction and endocrine function. Pathogenic variants in this gene are responsible for a wide spectrum of disorders/differences of sex development (DSD).

Methods: The molecular study involved Sanger sequencing, in vitro assays, and whole exome sequencing (WES).

Genomic variants reducing expression of two endocytic receptors in 46,XY differences of sex development.

Transporter-dependent steroid hormone uptake into target cells was demonstrated in genetically engineered mice and fruit flies. We hypothesized that mutations in such transporters may cause differences in sex development (DSD) in humans. Exome sequencing was performed in 16 genetically unsolved cases of 46,XY DSD selected from an anonymized collection of 708 lines of genital fibroblasts (GF) that were taken from individuals with incomplete virilization.