Insights into the molecular mechanisms underlying Houge-Janssens syndrome type 1: towards treatment options

Houge-Janssens Syndrome type 1 (HJS1), discovered barely 10 years ago, is a rare, inborn cause of intellectual disability, developmental delay and dysmorphic features, often associated with epilepsy and autism. The disorder is caused by a ‘spell of nature’, i.e. a small mistake in a single gene (PPP2R5D), and that is absent in both parents (de novo mutation). The affected gene encodes a signaling protein with incompletely understood functions in brain development and function. Due to their hampered functionality, HJS1 variants likely cause altered neuronal signaling, which, in principle, would be targetable by existing drugs. In this project, two roads towards identifying such mechanism-based treatment options will be followed. First, preliminary data from the lab have highlighted that the HJS1 variants undergo unexplained, altered chemical modifications (phosphorylation) that may contribute to their pathogenic effect. Firstly these modifications will be identified, and their regulatory and functional role in the normal PPP2R5D protein, before embarking on their effects in the HJS1 variants, and on restoring their normal patterns by targeted drugs. Second, there will be an experimentally determination of the role of PPP2R5D in human brain development and how the most recurrent HJS1 variant (E198K) may alter this, using brains-in-a-dish (brain organoids) - which will be generated from human stem cells. A comprehensive and comparative characterization of these mini-brains at the morphologic, molecular and signaling level will allow the identification of druggable pathways, which upon targeting, may reverse the observed HJS1 phenotype(s). Thus, this project will contribute to providing targeted treatments for HJS1, improving currently used symptomatic approaches.