A team of researchers has completed an exciting new study that reveals the inner workings of gene mutations that result in an ultra-rare syndrome with fewer than 100 reported cases since its first description in the early 1960s.

The hard-won research discovery may accelerate the development of a treatment for Borjeson-Forssman-Lehmann Syndrome (BFLS), a neurodevelopmental disorder linked to the X chromosome that’s characterized by seizures, intellectual disability, and behavioural disturbances. Children born with this devastating disease typically also exhibit physical symptoms including distinctive facial features and growth defects such as tapered fingers.

Published in EMBO Reports, the rigorous study’s results could likely have broader impact, potentially brightening treatment prospects for other rare X-linked neurodevelopmental syndromes.  

“The study of rare diseases of neurodevelopmental disorders and cognitive impairments advances our understanding of underlying mechanisms of disease pathogenesis and lays the foundation for the design of novel therapeutics,” says the senior author.

The project started by characterizing PHF6 gene regulation of the genome in the developing cortex of an embryonic mouse brain, according to the author. Employing computational approaches and multiomics, a biological analysis approach that provides nuanced data on how biological systems interact, they identified a panel of ephrin receptors as direct downstream targets.

The authors used several different mouse models of the disease and established that they exhibited altered neural stem cells and progenitor populations, as well as deregulation of ephrin receptors, which are proteins involved in wide range of processes in developing human embryos.

The consequence of this phenomenon is that the “Eph-A” family of receptors are a viable transcriptional target of the PHF6 gene and may “represent a therapeutically exploitable target” for BFLS and other X-linked intellectual disability disorders (XLID).

“The goal is to translate these discoveries into practical applications that could benefit individuals affected by XLID and other cognitive disorders stemming from neural stem cell misregulation,” the author says.

https://www.embopress.org/doi/full/10.1038/s44319-024-00082-0

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fphf6-mediated&filter=22