THE KEY ROLE OF SUMOYLATION IN THE OPHN1-RELATED PATHOLOGY OF INTELLECTUAL DISABILITY

Actin remodeling is essential for neuronal development and synaptic function and is tightly regulated by several proteins, including Rho GTPase-activating proteins (GAPs). OPHN1 is a Rho-GAP protein that plays a key role in neurons by regulating actin organization, dendritic spine development, synaptic architecture, and AMPAR trafficking. Mutations in the OPHN1 gene are associated with X-linked intellectual disability (X-LID), a developmental disorder characterized by neuronal abnormalities that lead to cognitive and social impairments.
Although OPHN1 function at synapses has been characterized, the molecular mechanisms regulating its activation, which depend on its structural conformation, are poorly investigated.
We identify OPHN1 as a novel target of SUMOylation, a post-translational modification that controls its autoinhibitory state. SUMO1 binding to lysine (K403) induces a conformational change that promotes OPHN1 activation and proper synaptic localization.
We show that the G412D missense mutation, identified in a patient with ID, stabilizes OPHN1 in an aberrant open conformation due to electrostatic repulsion between two aspartate residues. This alteration impairs SUMOylation, disrupting OPHN1 targeting to dendritic spines and leading to synaptic defects. Neurons expressing the mutant protein display disorganized actin cytoskeleton, increased spine density with abnormal morphology.
Interestingly, the introduction of the D441A mutation, inducing a charge neutralization, restores the native closed conformation of OPHN1. This rescues SUMO conjugation and restores OPHN1 physiological functions at synapses.
Our findings reveal a bidirectional relationship between protein conformation and SUMOylation in regulating OPHN1 neuronal functions. Disruption of this finely tuned interplay provides a mechanistic explanation for the ID neuronal phenotype.