Non-synonymous single nucleotide polymorphisms (nsSNPs) within the extracellular domains of the GPM6A gene impair...

Psychiatric disorders are complex pathologies influenced by both environmental and genetic factors, ultimately leading to synaptic plasticity dysfunction. Altered expression levels of neuronal glycoprotein GPM6a or polymorphisms within the GPM6A gene are associated with neuropsychiatric disorders like schizophrenia, depression, and claustrophobia. This protein promotes neurite outgrowth, filopodia formation, dendritic spine, and synapse maintenance in vitro. Although strong evidence suggests that its extracellular domains (ECs) are responsible for its function, the molecular mechanisms linking GPM6a to the onset of such diseases remain unknown. To gain knowledge of these mechanisms, we characterized new non-synonymous polymorphisms (nsSNPs) within the ECs of GPM6a. We identified six nsSNPs (T71P, T76I, M154V, F156Y, R163Q, and T210N) that impair GPM6a-induced plasticity in neuronal cultures without affecting GPM6a expression, folding, and localization to the cell membrane. However, we observed that some of these modified GPM6a's distribution at the cell membrane. Additionally, one of the nsSNPs exhibited alterations in GPM6a oligomerization, highlighting the importance of this amino acid in establishing homophilic cis interactions. Furthermore, we observed that the ability of GPM6a's extracellular domains to interact and induce cell aggregation was significantly decreased in several of the nsSNP variants studied here. Altogether, these results provide new insights into the key residues within GPM6a's extracellular regions that are crucial for its self-association, which is essential for promoting neuronal morphogenesis. Besides, these findings highlight the importance of reverse genetics approaches to gain knowledge on GPM6a's mechanisms of action and the genetic susceptibility of certain GPM6A variants.