RESUMEN
BACKGROUND: Several genetic alterations, including point mutations and copy number variations in NLGN genes, have been associated with psychiatric disorders, such as autism spectrum disorder (ASD) and X-linked mental retardation (XLMR). NLGN genes encode neuroligin (NL) proteins, which are adhesion molecules that are important for proper synaptic formation and maturation. Previously, we and others found that the expression level of murine NL1 is regulated by proteolytic processing in a synaptic activity-dependent manner. METHODS: In this study, we analyzed the effects of missense variants associated with ASD and XLMR on the metabolism and function of NL4X, a protein which is encoded by the NLGN4X gene and is expressed only in humans, using cultured cells, primary neurons from rodents, and human induced pluripotent stem cell-derived neurons. RESULTS: NL4X was found to undergo proteolytic processing in human neuronal cells. Almost all NL4X variants caused a substantial decrease in the levels of mature NL4X and its synaptogenic activity in a heterologous culture system. Intriguingly, the L593F variant of NL4X accelerated the proteolysis of mature NL4X proteins located on the cell surface. In contrast, other variants decreased the cell-surface trafficking of NL4X. Notably, protease inhibitors as well as chemical chaperones rescued the expression of mature NL4X. LIMITATIONS: Our study did not reveal whether these dysfunctional phenotypes occurred in individuals carrying NLGN4X variant. Moreover, though these pathological mechanisms could be exploited as potential drug targets for ASD, it remains unclear whether these compounds would have beneficial effects on ASD model animals and patients. CONCLUSIONS: These data suggest that reduced amounts of the functional NL4X protein on the cell surface is a common mechanism by which point mutants of the NL4X protein cause psychiatric disorders, although different molecular mechanisms are thought to be involved. Furthermore, these results highlight that the precision medicine approach based on genetic and cell biological analyses is important for the development of therapeutics for psychiatric disorders.
Asunto(s)
Trastorno Autístico/genética , Moléculas de Adhesión Celular Neuronal/genética , Mutación/genética , Sinapsis/patología , Secuencia de Aminoácidos , Animales , Moléculas de Adhesión Celular Neuronal/química , Moléculas de Adhesión Celular Neuronal/metabolismo , Membrana Celular/metabolismo , Células Cultivadas , Predisposición Genética a la Enfermedad , Células HEK293 , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Discapacidad Intelectual Ligada al Cromosoma X/genética , Ratones , Mutación Missense/genética , Neuronas/metabolismo , Organogénesis , Ratas WistarRESUMEN
A 62-year-old woman was hospitalized with complaints of right upper abdominal discomfort. Various imaging studies showed an extremely large suprarenal mass with solitary cystic formation. Partial adrenalectomy was successfully performed through the transperitoneal approach. The resected mass measured 12 x 10 x 10 cm and weighed 600 g. A pathological examination showed an Antoni-B predominant-type benign schwannoma containing a large volume of degenerative fluid. Our search of literature yielded few reports of solitary cystic schwannomas in the retroperitoneal cavity or throughout the body. This unusual cystic manifestation is thought to be a terminal stage of degeneration of a long-standing schwannoma.
