Disruption of the Homer1 coiled-coiled domain by a novel de novo human HOMER1 variant impairs protein scaffolding, calcium signalling, and synaptogenesis
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…
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.
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