ESPEYB20 12. The Year in Science and Medicine Basic Research (3 abstracts)
12.9. Formin-mediated nuclear actin at androgen receptors promotes transcription
Knerr J , Werner R , Schwan C , Wang H , Gebhardt P , Grotsch H , Caliebe A , Spielmann M , Holterhus PM , Grosse R & Hornig NC
Nature 2023 Vol. 617 Issue 7961 Pages 616–622. https://doi.org/10.1038/s41586-023-05981-1
Brief summary: Two unrelated patients with a disorder of sex development (DSD) phenotype of partial androgen insensitivity (PAIS) showed heterozygous variants in the DAAM2 gene. Their genital skin fibroblasts showed reduced dihydrotestosterone-stimulated androgen receptor (AR) activity. Extensive basic studies revealed the underlying mechanism of the DSD in which DAAM2-regulated actin polymerization at the ligand-inducible androgen receptor is required for androgen-stimulated AR activation.
DSD due to androgen insensitivity/resistance syndrome (AIS) is one of the most common causes of 46,XY DSD. AR gene variants with complete loss of function lead to complete AIS and sex reversal, while partial activity (PAIS) can manifest with a broad range of DSD phenotypes. However, AR gene variants are found in less than half of individuals with a PAIS phenotype. Previously, the same group of researchers reported that aberrant CpG methylation within the proximal AR promoter plays an important role in the control of AR gene expression (1). In this current report, they show that even factors that indirectly regulate the androgen-stimulated AR included in the DNA polymerization machinery for gene transcription can have a crucial effect on its gene expression and function.
To date, half of investigated patients with a 46,XY DSD remain without molecular diagnosis when using whole exome sequencing and/or array CGH and an ‘opinionated’ analytical pipeline. This work illustrates very nicely where we can find additional regulatory factors of known DSD genes playing important roles in sex development.
Reference: 1. Epigenetic repression of androgen receptor transcription in mutation-negative androgen insensitivity syndrome (AIS Type II). Nadine C Hornig et al. J Clin Endocrinol Metab. 2018 Dec 1;103(12):4617–4627. doi: 10.1210/jc.2018-00052.
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ESPE Yearbook of Paediatric Endocrinology
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