{
  "id": 218775,
  "title": "Disruption of the Homer1 coiled-coiled domain by a novel de novo human HOMER1 variant impairs protein scaffolding, calcium signalling, and synaptogenesis",
  "url": "https://urgent.news/2026/08/06/disruption-of-the-homer1-coiled-coiled-domain-by-a-novel-de-novo",
  "topic": "culture",
  "section": "Culture",
  "published": "2026-08-06T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.08.05.741753v1?rss=1"
  },
  "original_language": "en",
  "account": "A novel de novo human HOMER1 variant, HOMER1-R297W, has been discovered to disrupt protein scaffolding, calcium signaling, and synaptogenesis. This mutation, which alters the Homer1b/c protein, leads to a dominant-negative effect on functions dependent on Homer1. In sensory neurons found in the dorsal root ganglion, Homer1b/c-R297W impairs axonal growth cone turning towards gradients of brain-derived neurotrophic factor, a process requiring functional store-operated calcium entry. This defect in store-operated calcium entry is also observed in hippocampal neurons, resulting in reduced dendritic spine density and diminished endoplasmic reticulum infiltration into spines. Synaptic metabotropic glutamate receptor 5 expression is also decreased, accompanied by blunted dendritic calcium increases following group-I mGluR activation. Super resolution imaging reveals that Homer1b/c-R297W diminishes receptor clustering, disconnecting it from essential binding partners such as IP3R, mGluR5, and STIM1/2. These findings underscore the critical role of Homer1b/c's tetrameric scaffolding in axon guidance, dendritic spine dynamics, and synaptic calcium signaling. By disrupting these processes, Homer1b/c-R297W provides valuable mechanistic insights into how rare de novo variants and altered protein scaffolding can contribute to connectivity deficits observed in neurodevelopmental and neurological disorders.",
  "summary": "Rare de novo variants in synaptic scaffolding proteins are increasingly recognized for their roles in driving abnormal neuronal connectivity underlying conditions such as epilepsy and autism spectrum disorder (ASD). Homer1b/c, a synaptic scaffolding protein, regulates a wide suite of synaptic functions including Ca2+ signaling, dendritic spine morphogenesis and multiple forms of synaptic…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}